Template-fixed beta-hairpin peptidomimetics with cxcr4 antagonizing activity

ABSTRACT

Template-fixed peptidomimetics formula (Ia) formula (Ib) wherein Z is a template-fixed chain of 14 α-amino and/or α-hydroxy acid residues which, depending on their positions in the chain (counted starting from the N-terminal amino acid), are Pro, Gly, a glycolic acid residue or of certain types which, as the remaining symbols in the above formulae, are defined in the description and the claims, and salts thereof, have CXCR4 antagonizing properties and can be used for preventing HIV infections in non-infected individuals or for slowing and halting viral progression in infected patients; or where cancer is mediated or resulting from CXCR4 receptor activity; or where immunological diseases are mediated or resulting from CXCR4 receptor activity; or for treating immuno suppression; or during apheresis collections of peripheral blood stem cells and/or as agents to induce mobilization of stem cells to regulate tissue repair. These depsipeptides can be manufactured by a process which is based on a mixed solid- and solution phase synthetic strategy.

The present invention provides template-fixed β-hairpin peptidomimeticsincorporating template-fixed chains of 14 α-amino acid residues which,depending on their positions in the chains, are Pro, Gly, a Glycolicacid residue or of certain types, as defined herein below, at least oneof these α-amino acid residues being replaced by an α-hydroxy acidresidue of a certain type, as defined herein below, and/or the templatecontaining such α-hydroxy acid residue. These template-fixeddepsipeptides have CXCR4 antagonizing activity. In addition, the presentinvention provides an efficient synthetic process by which thesecompounds can, if desired, be made in parallel library-format. Theseβ-hairpin peptidomimetics show improved efficacy, bioavailability, andmost importantly a significantly enhanced ratio between CXCR4antagonizing activity on the one hand, and hemolysis on red blood cellsand cytotoxicity on the other.

Many medically significant biological processes are mediated by signaltransduction that involves chemokines and their receptors in general andstromal derived factor 1 (SDF-1/CXCL12)and its receptor CXCR4 inparticular.

CXCR4 and its ligand SDF-1 are involved in trafficking of B cells,hematopoietic stem cells (HSC) and hematopoietic progenitor cells (HPC).For instance, CXCR4 is expressed on CD34+ cells, and has been implicatedin the process of CD34+ cell migration and homing (S. M. Watt, S. P.Forde, Vox sanguinis 2008, 94, 18-32). It has also been shown that theCXCR4 receptor plays an important role in the release of stem andprogenitor cells from the bone marrow to the peripheral blood (L. M.Pelus, S. Fukuda, Leukemia 2008, 22, 466-473). This activity of CXCR4could be very important for efficient apheresis collections ofperipheral blood stem cells. Autologous peripheral blood cells provide arapid and sustained hematopoietic recovery followingauto-transplantation after the administration of high-dose chemotherapyor radiotherapy in patients with haematological malignancies and solidtumors. (W. C. Liles et al., Blood 2003, 102, 2728-2730).

Recently, it has been demonstrated that SDF-1 is locally up-regulated inanimal models of injury including focal ischemic stroke, global cerebralischemia, myocardial infarction and hind limb ischemia as well as beinginvolved in recovery after peripheral ischemia or following injury tothe liver, kidney or lung (A. E. Ting, R. W. Mays, M. R. Frey, W. Van'tHof, S. Medicetty, R. Deans, Critical Reviews in Oncology/Hematology2008, 65, 81-93 and literature cited herein; F. Lin, K. Cordes, L. Li,L. Hood, W. G. Couser, Shankland et al., J. Am. Soc. Nephrol. 2003, 14,1188-1199; C. C. Dos Santos, Intensive Care Med. 2008, 34, 619-630).These results suggest that SDF-1 may chemoattract CXCR4-positive stemcells for tissue and organ repair/regeneration (M. Z. Ratajczak, M.Kucia, R. Reca, M. Majka, A. Janowska-Wieczorek, J. Ratajczak, Leukemia2004, 18, 29-40). Therefore, modulating the SDF-1/CXCR4 axis by CXCR4inhibitors should result in a significant therapeutic benefit by usingreleased stem cells to regulate tissue repair.

There is increasing evidence that implies that chemokines in general andthe SDF-1/CXCR4 interaction in particular plays a pivotal role inangiogenesis. Chemokines induce angiogenesis directly by binding theircognate receptors on endothelial cells or indirectly by promotinginflammatory cell infiltrates, which deliver other angiogenic stimuli. Anumber of proinflammatory chemokines including interleukin 8 (IL-8),growth-regulated oncogene, stromal cell-derived factor 1 (SDF-1),monocyte chemotactic protein 1 (MCP-1), eotaxin 1, and 1-309 have beenshown to act as direct inducers of angiogenesis. (X. Chen, J. A.Beutler, T. G. McCloud, A. Loehfelm, L. Yang, H.F. Dong, O. Y. Chertov,R. Salcedo, J. J. Oppenheim, O. M. Howard. Clin. Cancer Res. 2003, 9(8),3115-3123; R. Salcedo, J. J. Oppenheim, Microcirculation 2003, (3-4),359-370).

Recently obtained results show that the CXCR4 receptor is involved inthe chemotactic activity of cancer cells, such as breast cancermetastasis or in metastasis of ovarian cancer (A. Muller, B. Homey, H.Soto, N. Ge, D. Catron, M. E. Buchanan, T. Mc Clanahan, E. Murphey, W.Yuan, S. N. Wagner, J. L. Barrera, A. Mohar, E. Verastegui, A. Zlotnik,Nature 2001, 50, 410; J. M. Hall, K. S. Korach, Molecular Endocrinology2003, 17, 792-803.), Non-Hodgin's Lymphoma (F. Bertolini, C.Dell'Agnola, P. Manusco, C. Rabascio, A. Burlini, S. Monestiroli, A.Gobbi, G. Pruneri, G. Martinelli, Cancer Research 2002, 62, 3106-3112),or lung cancer (T. Kijima, G. Maulik, P. C. Ma, E. V. Tibaldi, R. E.Turner, B. Rollins, M. Sattler, B. E. Johnson, R. Salgia, CancerResearch 2002, 62, 6304-6311), melanoma, prostate cancer, kidney cancer,neuroblastomia, pancreatic cancer, multiple myeloma, chronic lymphocyticleukemia (H. Tamamura et al., FEBS Letters 2003, 550, 79-83, citedref.). Blocking the chemotactic activity with a CXCR4 inhibitor shouldstop the migration of cancer cells.

CXCR4 has also been implicated in the growth and proliferation oftumors. It was shown that activation of the CXCR4 receptor was criticalfor the growth of both malignant neuronal and glial tumors, and smallcell lung tumors. Moreover, systemic administration of the CXCR4antagonist AMD3100 inhibits growth of intracranial glioblastoma andmedulloblastoma xenografts by increasing apoptosis and decreasing theproliferation of tumor cells (J. B. Rubin, A. L Kung, R. S Klein, J. A.Chan, Y. Sun, K. Schmidt, M. W. Kieran, A. D. Luster, R. A. Segal, ProcNatl Acad Sci USA. 2003, 100(23),13513-13518, S. Barbero, R. Bonavia, A.Bajetto, C. Porcile, P. Pirani, J. L. Ravetti, G. L. Zona, R. Spaziante,T. Florio, G. Schettini, Cancer Res. 2003, 63(8), 1969-1974, T. Kijima,G. Maulik, P. C. Ma, E. V. Tibaldi, R. E. Turner, B. Rollins, M.Sattler, B. E. Johnson, R. Salgia. Cancer Res. 2002, 62(21), 6304-6311;F. Bertolini, C. Dell'Agnola, P. Mancuso, C. Rabascio, A. Burlini, S.Monestiroli, A. Gobbi, G. Pruneri, G. Martinelli Cancer Res. 2002,62(11), 3106-3112.

It is well established that chemokines are involved in a number ofinflammatory pathologies and some of them show a pivotal role in themodulation of osteoclast development. Immunostaining for SDF-1 (CXCL12)on synovial and bone tissue biopsies from both rheumatoid arthritis (RA)and osteoarthritis (OA) samples have revealed strong increases in theexpression levels of chemokines under inflammatory conditions (F.Grassi, S. Cristino, S. Toneguzzi, A. Piacentini, A. Facchini, G.Lisignoli, J. Cell Physiol. 2004; 199(2), 244-251). It seems likely thatthe CXCR4 receptor plays an important role in inflammatory diseases suchas rheumatoid arthritis, asthma, or multiple sclerosis (K. R. Shadidi etal., Scandinavian Journal of Immunology 2003, 57, 192-198; J. A.Gonzalo, J. Immunol. 2000, 165, 499-508; S. Hatse et al., FEBS Letters2002, 527, 255-262 and cited references). The mediation of recruitmentof immune cells to sites of inflammation should be stopped by a CXCR4inhibitor.

To date the available therapies for the treatment of HIV infections havebeen leading to a remarkable improvement in symptoms and recovery fromdisease in infected people. Although the highly active anti retroviraltherapy (HAART) which involves a combination of reversetranscriptase/protease-inhibitor has dramatically improved the clinicaltreatment of individuals with AIDS or HIV infection, there have stillremained several serious problems including multi drug resistance,significant adverse effects and high costs. Particularly desired areanti HIV agents that block the HIV infection at an early stage of theinfection, such as the viral entry. It has recently been recognized thatfor efficient entry into target cells, human immunodeficiency virusesrequire the chemokine receptors CCR5 and CXCR4 as well as the primaryreceptor CD4 (N. Levy, Engl. J. Med. 1996, 335, 1528-1530). Accordingly,an agent which could block the CXCR4 chemokine receptors should preventinfections in non-infected individuals and slow or halt viralprogression in infected patients (J. Cohen, Science 1997, 275,1261-1264).

Among the different types of CXCR4 inhibitors (M. Schwarz, T. N. C.Wells, A. E. I. Proudfoot, Receptors and Channels 2001, 7, 417-428), oneemerging class is based on naturally occurring cationic peptideanalogues derived from Polyphemusin II which have an antiparallelβ-sheet structure, and a β-hairpin that is maintained by two disulfidebridges (H. Nakashima, M. Masuda, T. Murakami, Y. Koyanagi, A.Matsumoto, N. Fujii, N. Yamamoto, Antimicrobial Agents and Chemoth.1992, 36, 1249-1255; H. Tamamura, M.

Kuroda, M. Masuda, A. Otaka, S. Funakoshi, H. Nakashima, N. Yamamoto, M.Waki, A. Matsumotu, J. M. Lancelin, D. Kohda, S. Tate, F. Inagaki, N.Fujii, Biochim. Biophys. Acta 1993, 209, 1163; WO 95/10534 Al).

Synthesis of structural analogs and structural studies by nuclearmagnetic resonance (NMR) spectroscopy have shown that the cationicpeptides adopt well defined β-hairpin conformations, due to theconstraining effect of the one or two disulfide bridges (H. Tamamura, M.Sugioka, Y. Odagaki, A. Omagari, Y. Kahn, S. Oishi, H. Nakashima, N.Yamamoto, S.C. Peiper, N. Hamanaka, A. Otaka, N. Fujii, Bioorg. Med.Chem. Lett. 2001, 359-362). These results show that the β-hairpinstructure plays an important role in CXCR4 antagonizing activity.

Additional structural studies have also indicated that the antagonizingactivity can also be influenced by modulating amphiphilic structure andthe pharmacophore (H. Tamamura, A. Omagari, K. Hiramatsu,. K. Gotoh, T.Kanamoto, Y. Xu, E. Kodama, M. Matsuoka, T. Hattori, N. Yamamoto, H.Nakashima, A. Otaka, N. Fujii, Bioorg. Med. Chem. Lett. 2001, 11,1897-1902; H. Tamamura, A. Omagari, K. Hiramatsu, S. Oishi, H.Habashita, T. Kanamoto, K. Gotoh, N. Yamamoto, H. Nakashima, A. Otaka N.Fujii, Bioorg. Med. Chem. 2002, 10, 1417-1426; H. Tamamura, K.Hiramatsu, K. Miyamoto, A. Omagari, S. Oishi, H. Nakashima, N. Yamamoto,Y. Kuroda, T. Nakagawa, A. Otaki, N. Fujii, Bioorg. Med. Chem. Letters2002, 12, 923-928).

A key issue in the design of CXCR4 antagonizing peptides is selectivity.The polyphemusin II derived analogs exert still cytotoxicity despiteimprovements (K. Matsuzaki, M. Fukui, N. Fujii, K. Miyajima, Biochim.Biophys. Acta 1991, 259, 1070; A. Otaka, H. Tamamura, Y. Terakawa, M.Masuda, T. Koide, T. Murakami, H. Nakashima, K. Matsuzaki, K. Miyajima,T. Ibuka, M. Waki, A. Matsumoto, N. Yamamoto, N. Fujii Biol. Pharm.Bull. 1994, 17, 1669 and cited references above). This cytotoxicactivity essentially obviates its use in vivo and represents a seriousdisadvantage in clinical applications. Before intravenous use can beconsidered, the general toxicity, protein-binding activity in bloodserum, as well as protease stability become serious issues which must beadequately addressed.

In the compounds described below, a new strategy is introduced tostabilize beta-hairpin conformations in cyclic template-stabilizedpeptidomimetics exhibiting high CXCR4 antagonizing activity, beinguseful for efficient apheresis collections of mobilized peripheral bloodstem cells and/or using these mobilized cells to regulate tissue repair,and having anticancer activity, anti inflammatory activity and anti HIVactivity. This strategy involves transplanting the cationic andhydrophobic hairpin sequence onto a template, whose function is torestrain the peptide loop backbone into hairpin geometry. The rigidityof the hairpin may be further influenced by introducing a disulfidebridge. In addition, incorporation of structural elements derived fromα-hydroxy acids into template-bound hairpin mimetics generatingdepsipeptides has been realized, a new approach which has not previouslybeen evaluated for development of β-hairpin peptidomimetics with CXCR4antagonizing activity.

Depsipeptides comprise a broad family of cyclic molecules containingamino and hydroxy acid residues connected by amide and ester bonds (V.T. Ivanov, I. I. Mikhaleva in Houben-Weyl, “Synthesis of Peptides andPeptidomimetics”, Editor-in-Chief: M. Goodman, Editors: A. Felix, L.Moroder, C. Toniolo, 2004, Georg Thieme Verlag, Stuttgart, Bd. E22c,272-291). Moreover, the vast majority of natural depsipeptides exhibit adiverse range of biological activities including antitumor, antiviral,antiinflammatory, immunosuppressant, antibiotic and antifungalactivities of pharmacological and medical relevance (F. Sarabia, S.Chammaa, A. S. Ruiz, L. M. Ortiz, F. J. Lopez Herrera, Curr. Med. Chem.2004, 11, 1309-1332 and ref. cited herein; Y. Hamada, T. Shioiri, Chem.Rev. 2005, 105, 4441-4482).

Cyclic depsipeptide natural products are generally less stable towardschemical and enzymatic proteolysis in vitro and in vivo than the parentcyclic peptides (Review: F. von Nussbaum, M. Brands, B. Hinzen, S.Weigand, D. Häbich, Angew. Chem. Int. Ed. 2006, 45, 5072-5129;Lysobactin/Katanosin: A. A. Tymiak, T. J. McCormick, S. E. Unger, J.Org. Chem. 1989, 54, 1149-1157; Enopeptins: H. Brötz-Oesterhelt, D.Beyer, H. P. Kroll, R. Endermann, C. Ladel, W. Schroeder, B. Hinzen, S.Raddatz, H. Paulsen, K. Hennenger, J. E. Baldow, H. G. Sahl, H.Labischinski, Nat. Med. 2005, 11, 1082-1087; Aureobasidin: T. Kurome, T.Inoue, K. Takesako, I. Kato, J. Antibiot. 1998, 51, 359-367). This isalso generally the case for template-fixed β-hairpin mimeticdepsipeptides, although stable representatives are available as well.

A reduced in vivo proteolytic stability of some of the present cyclicdepsipetides, however, might be beneficial for therapeutic applicationssuch as hematopoetic stem cell transplantation and tissue repair where arapid onset of biological activity and relatively fast clearance of thecompounds could be an advantage.

Template-bound hairpin mimetic peptides have been described in theliterature (D. Obrecht, M. Altorfer, J. A. Robinson, Adv. Med. Chem.1999, 4, 1-68; J. A. Robinson, Syn. Lett. 2000, 4, 429-441), and theability to generate β-hairpin peptidomimetics using combinatorial andparallel synthesis methods has now been established (L. Jiang, K.Moehle, B. Dhanapal, D. Obrecht, J. A. Robinson, Helv. Chim. Acta. 2000,83, 3097-3112). However, the additional incorporation of structureelements derived from α-hydroxy acids into template-bound hairpinmimetics by applying and altering these methods has not previously beenevaluated for development of CXCR4 antagonizing peptides. The methodsdescribed here allow the synthesis and screening of large hairpinmimetic libraries, which in turn considerably facilitatesstructure-activity studies, and hence the discovery of new moleculeswith highly potent CXCR4 antagonizing activity or anti cancer activityor anti inflammatory activity or anti HIV activity and low hemolyticactivity to human red blood cells.

β-Hairpin peptidomimetics obtained by the approach described here can beused in apheresis collections of peripheral blood stem cells and/or asagents to induce mobilization of stem cells to regulate tissue repair orare useful as anticancer agents, as inhibitors of tumor growth or asapoptosis inducing agents, as anti-metastasis agents, as antiinflammatory agents and as anti-HIV agents.

The β-hairpin peptidomimetics of the present invention are compounds ofthe general formulae

wherein

are groups of one of the formulae

wherein

is Gly or a Glycolic acid residue, or the residue of an L-α-amino acidwith B being a residue of formula —NR²⁰CH (R⁷¹)—, or —NR²⁰CH(R⁷²)—, or—NR²⁰CH(R⁷³)— or —NR²⁰CH(R⁷⁴)— or —NR^(H)CH(R⁸⁴)— or the residue of anL-α-hydroxy acid with B being a residue of formula —OCH(R⁷¹)— or—OCH(R⁷²)— or —OCH(R⁷³)— or —OCH(R⁷⁴)— or —OCH(R⁸⁴)—, or the enantiomerof one of the groups A1 to A69 and A105, or the enantiomer of the groupsA106 to A110 as defined hereinafter;

is a group of one of the formulae

-   -   R¹ is H; lower alkyl; or aryl-lower alkyl;    -   R² is H; alkyl; alkenyl; —(CH₂)_(m)(CHR⁶¹)_(s)OR⁵⁵;        —(CH₂)_(m)(CHR⁶¹)_(s)SR⁵⁶; —(CH₂)_(m)(CHR⁶¹)_(s)NR³³R³⁴;        —(CH₂)_(m)(CHR⁶¹)_(s)OCONR³³R⁷⁵;        —(CH₂)_(m)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷;        —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂;        —(CH₂)_(o)(CHR⁶¹)_(s)SO₂R⁶²; or —(CH₂)_(o)(CHR⁶¹)_(s)R⁷⁷;    -   R³ is H; alkyl; alkenyl; —(CH₂)_(m)(CHR⁶¹)_(s)OR⁵⁵;        —(CH₂)_(m)(CHR⁶¹)_(s)SR⁵⁶; —(CH₂)_(m)(CHR⁶¹)_(s)NR³³R³⁴;        —(CH₂)_(m)(CHR⁶¹)_(s)OCONR³³R⁷⁶;        —(CH₂)_(m)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷;        —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂;        —(CH₂)_(o)(CHR⁶¹)_(s)SO₂R⁶²; or —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸;    -   R⁴ is H; alkyl; alkenyl; —(CH₂)_(m)(CHR⁶¹)_(s)OR⁶⁵;        —(CH₂)_(m)(CHR⁶¹)_(s)

SR⁵⁶; —(CH₂)_(m)(CHR⁶¹)_(s)NR³³R³⁴; —(CH₂)_(m)(CHR⁶¹)_(s)OCONR³³R⁷⁵;—(CH₂)_(m)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(p)(CHR⁶¹)_(s)COOR⁵⁷;—(CH₂)_(p)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; —(CH₂)_(p)(CHR⁶¹)_(s)PO(OR⁶⁰)₂;—(CH₂)_(p)(CHR⁶¹)_(s)SO₂R⁶²; or —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸;

-   -   R⁵ is alkyl; alkenyl; —(CH₂)_(o)(CHR⁶¹)_(s)OR⁵⁶;        —(CH₂)_(o)(CHR⁶¹)_(s)SR⁶⁶; —(CH₂)_(o)(CHR⁶¹)_(s)NR³³R³⁴;        —(CH₂)_(o)(CHR⁶¹)_(s)OCONR³³R⁷⁵;        —(CH₂)_(o)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷;        —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂;        —(CH₂)_(o)(CHR⁶¹)_(s)SO₂R⁶²; or —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸;    -   R⁶ is H; alkyl; alkenyl; —(CH₂)_(o)(CHR⁶¹)_(s)OR⁵⁵;        —(CH₂)_(o)(CHR⁶¹)_(s)SR⁶⁶; —(CH₂)_(o)(CHR⁶¹)_(s)NR³³R³⁴;        —(CH₂)_(o)(CHR⁶¹)_(s)OCONR³³R⁷⁵;        —(CH₂)_(o)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷;        —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂;        —(CH₂)_(o)(CHR⁶¹)_(s)SO₂R⁶²; or —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸;    -   R⁷ is alkyl; alkenyl; —(CH₂)_(q)(CHR⁶¹)_(s)OR⁵⁵;        —(CH₂)_(q)(CHR⁶¹)_(s)NR³³R³⁴; —(CH₂)_(q)(CHR⁶¹)_(s)OCONR³³R⁷⁵;        —(CH₂)_(q)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(r)(CHR⁶¹)_(s)COOR⁵⁷;        —(CH₂)_(r)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; —(CH₂)_(r)(CHR⁶¹)_(s)PO(OR⁶⁰)₂;        —(CH₂)_(r)(CHR⁶¹)_(s)SO₂R⁸²; or —(CH₂)_(r)(CHR⁶¹)_(s)C₆H₄R⁸;    -   R⁸ is H; Cl; F; CF₃; NO₂; lower alkyl; lower alkenyl; aryl;        aryl-lower alkyl;        —(CH₂)_(o)(CHR⁶¹)_(s)R⁷⁷—(CH₂)_(o)(CHR⁶¹)_(s)OR⁵⁵;        —(CH₂)_(o)(CHR⁶¹)_(s)SR⁵⁶; —(CH₂)_(o)(CHR⁶¹)NR³³R³⁴;        —(CH₂)_(o)(CHR⁶¹)_(s)OCONR³³R⁷⁵;        —(CH₂)_(o)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷;        —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂;        —(CH₂)_(o)(CHR⁶¹)_(s)SO₂R⁶²; or —(CH₂)_(o)(CHR⁶¹)_(s)COR⁶⁴;    -   R⁹ is alkyl; alkenyl; —(CH₂)_(o)(CHR⁶¹)_(s)OR⁵⁵;        —(CH₂)_(o)(CHR⁶¹)_(s)SR⁵⁶; —(CH₂)_(o)(CHR⁶¹)_(s)NR³³R³⁴;        —(CH₂)_(o)(CHR⁶¹)_(s)OCONR³³R⁷⁵;        —(CH₂)_(o)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷;        —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂;        —(CH₂)_(o)(CHR⁶¹)_(s)SO₂R⁶²; or —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸;    -   R¹⁰ is alkyl; alkenyl; —(CH₂)_(o)(CHR⁶¹)_(s)OR⁵⁵;        —(CH₂)_(o)(CHR⁶¹)_(s)SR⁵⁶; —(CH₂)_(o)(CHR⁶¹)_(s)NR³³R³⁴;        —(CH₂)_(o)(CHR⁶¹)_(s)OCONR³³R⁷⁵;        —(CH₂)_(o)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷;        —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂;        —(CH₂)_(o)(CHR⁶¹)_(s)SO₂R⁶²; or —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸;    -   R¹¹ is H; alkyl; alkenyl; —(CH₂)_(m)(CHR⁶¹)_(s)OR⁵⁵;        —(CH₂)_(m)(CHR⁶¹)_(s)NR³³R³⁴; —(CH₂)_(m)(CHR⁶¹)_(s)OCONR³³R⁷⁵;        —(CH₂)_(m)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷;        —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂;        —(CH₂)_(o)(CHR⁶¹)_(s)SO₂R⁶²; or —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸;    -   R¹² is H; alkyl; alkenyl; —(CH₂)_(m)(CHR⁶¹)_(s)OR⁵⁵;        —(CH₂)_(m)(CHR⁶¹)_(s)SR⁵⁶; —(CH₂)_(m)(CHR⁶¹)_(s)NR³³R³⁴;        —(CH₂)_(m)(CHR⁶¹)_(s)OCONR³³R⁷⁵;        —(CH₂)_(m)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(r)(CHR⁶¹)_(s)COOR⁵⁷;        —(CH₂)_(r)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; —(CH₂)_(r)(CHR⁶¹)_(s)PO(OR⁶⁰)₂;        —(CH₂)_(r)(CHR⁶¹)_(s)SO₂R⁶²; or —(CH₂)_(r)(CHR⁶¹)_(s)C₆H₄R⁸;    -   R¹³ is alkyl; alkenyl; —(CH₂)_(q)(CHR⁶¹)_(s)OR⁵⁵;        —(CH₂)_(q)(CHR⁶¹)_(s)SR⁵⁶; —(CH₂)_(q)(CHR⁶¹)_(s)NR³³R³⁴;        —(CH₂)_(q)(CHR⁶¹)_(s)OCONR³³R⁷⁵;        —(CH₂)_(q)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(q)(CHR⁶¹)_(s)COOR⁵⁷;        —(CH₂)_(q)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; —(CH₂)_(q)(CHR⁶¹)_(s)PO(OR⁶⁰)₂;        —(CH₂)_(q)(CHR⁶¹)_(s)SO₂R⁶²; or —(CH₂)_(q)(CHR⁶¹)_(s)C₆H₄R⁸;    -   R¹⁴ is H; alkyl; alkenyl; —(CH₂)_(m)(CHR⁶¹)_(s)OR⁵⁵;        —(CH₂)_(m)(CHR⁶¹)_(s)NR³³R³⁴; —(CH₂)_(m)(CHR⁶¹)_(s)OCONR³³R⁷⁵;        —(CH₂)_(m)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(q)(CHR⁶¹)_(s)COOR⁵⁷;        —(CH₂)_(q)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; —(CH₂)_(q)(CHR⁶¹)_(s)PO(OR⁶⁰);        —(CH₂)_(q)(CHR⁶¹)_(s)SOR⁶²; or —(CH₂)_(q)(CHR⁶¹)_(s)C₆H₄R⁵;    -   R¹⁵ is alkyl; alkenyl; —(CH₂)_(o)(CHR⁶¹)_(s)OR⁵⁵;        —(CH₂)_(o)(CHR⁶¹)_(s)SR⁵⁶; —(CH₂)_(o)(CHR⁶¹)_(s)NR³³R³⁴;        —(CH₂)_(o)(CHR⁶¹)_(s)OCONR³³R⁷⁵;        —(CH₂)_(o)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷;        —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂;        —(CH₂)_(o)(CHR⁶¹)_(s)SO₂R⁶²; or —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸;    -   R¹⁶ is alkyl; alkenyl; —(CH₂)_(o)(CHR⁶¹)_(s)OR⁵⁵;        —(CH₂)_(o)(CHR⁶¹)_(s)SR⁶⁶; —(CH₂)_(o)(CHR⁶¹)_(s)NR³³R³⁴;        —(CH₂)_(o)(CHR⁶¹)_(s)OCONR³³R⁷⁵;        —(CH₂)_(o)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷;        —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂;        —(CH₂)_(o)(CHR⁶¹)_(s)SO₂R⁶²; or —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸;    -   R¹⁷ is alkyl; alkenyl; —(CH₂)_(q)(CHR⁶¹)_(s)OR⁵⁵;        —(CH₂)_(q)(CHR⁶¹)_(s)SR⁵⁶; —(CH₂)_(q)(CHR⁶¹)_(s)NR³³R³⁴;        —(CH₂)_(q)(CHR⁶¹)_(s)OCONR³³R⁷⁵;        —(CH₂)_(q)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(q)(CHR⁶¹)_(s)COOR⁵⁷;        —(CH₂)_(q)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; —(CH₂)_(q)(CHR⁶¹)_(s)PO(OR⁶⁰)₂;        —(CH₂)_(q)(CHR⁶¹)_(s)SO₂R⁶²; or —(CH₂)_(q)(CHR⁶¹)_(s)C₆H₄R⁸;    -   R¹⁸ is alkyl; alkenyl; —(CH₂)_(p)(CHR⁶¹)_(s)OR⁵⁵;        —(CH₂)_(p)(CHR⁶¹)_(s)SR⁵⁶; —(CH₂)_(p)(CHR⁶¹)_(s)NR³³R³⁴;        —(CH₂)_(p)(CHR₆₁)_(s)OCONR³³R⁷⁵;        —(CH₂)_(p)(CHR⁶¹)_(s)NR²⁸CONR³³R⁸²; —(CH₂)_(p)(CHR⁶¹)_(s)COOR⁵⁷;        —(CH₂)_(p)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; —(CH₂)_(p)(CHR⁶¹)_(s)PO(OR⁶⁰)₂;        —(CH₂)_(p)(CHR⁶¹)_(s)SO₂R⁶²; or —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸;    -   R¹⁹ is lower alkyl; —(CH₂)_(p)(CHR⁶¹)_(s)OR⁵⁵;        —(CH₂)_(p)(CHR⁶¹)_(s)SR⁵⁶; —(CH₂)_(p)(CHR⁶¹)_(s)NR³³R³⁴;        —(CH₂)_(p)(CHR⁶¹)_(s)OCONR³³R⁷⁵;        —(CH₂)_(p)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(p)(CHR⁶¹)_(s)COOR⁵⁷;        —(CH₂)_(p)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; —(CH₂)_(p)(CHR⁶¹)_(s)PO(OR⁶⁰)₂;        —(CH₂)_(p)(CHR⁶¹)_(s)SO₂R⁶²; or —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸; or    -   R¹⁸ and R¹⁹ taken together can form: —(CH₂)₂₋₆—;        —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—;    -   R²⁰ is H; li alkyl; alkenyl; or aryl-lower alkyl;    -   R²¹ is H; alkyl; alkenyl; —(CH₂)_(o)(CHR⁶¹)_(s)OR⁵⁵;        —(CH₂)_(o)(CHR⁶¹)_(s)SR⁵⁶; —(CH₂)_(o)(CHR⁶¹)_(s)NR³³R³⁴;        —(CH₂)_(o)(CHR⁶¹)_(s)OCONR³³R⁷⁵;        —(CH₂)_(o)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷;        —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂;        —(CH₂)_(o)(CHR⁶¹)_(s)SO₂R⁶²; or —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸;    -   R²² is H; alkyl; alkenyl; —(CH₂)_(o)(CHR⁶¹)_(s)OR⁵⁵;        —(CH₂)_(o)(CHR⁶¹)_(s)SR⁵⁶; —(CH₂)_(o)(CHR⁶¹)_(s)NR³³R³⁴;        —(CH₂)_(o)(CHR⁶¹)_(s)OCONR³³R⁷⁵;        —(CH₂)_(o)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷;        —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂;        —(CH₂)_(o)(CHR⁶¹)_(s)SO₂R⁶²; or —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸;    -   R²³ is alkyl; alkenyl; —(CH₂)_(o)(CHR⁶¹)_(s)R⁵⁵;        —(CH₂)_(o)(CHR⁶¹)_(SR) ⁵⁶; —(CH₂)_(o)(CHR⁶¹)_(s)NR³³R³⁴;        —(CH₂)_(o)(CHR⁶¹)_(s)OCONR³³R⁷⁵;        —(CH₂)_(o)(CHR⁶¹)_(s)NR²⁰CONR³³R⁹²; —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷;        —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂;        —(CH₂)_(o)(CHR⁶¹)_(s)SO₂R⁶²; or —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁵;    -   R²⁴ is alkyl; alkenyl; —(CH₂)_(o)(CHR⁶¹)_(s)OR⁵⁵;        —(CH₂)_(o)(CHR⁶¹)_(s)SR⁵⁶; —(CH₂)_(o)(CHR⁶¹)_(s)NR³³R³⁴;        —(CH₂)_(o)(CHR⁶¹)_(s)OCONR³³R⁷⁵;        —(CH₂)_(o)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷;        —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂;        —(CH₂)_(o)(CHR⁶¹)_(s)SO₂R⁶²; or —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸;    -   R²⁵ is H; alkyl; alkenyl; —(CH₂)_(m)(CHR⁶¹)_(s)OR⁵⁵;        —(CH₂)_(m)(CHR⁶¹)_(s)SR⁵⁶; —(CH₂)_(m)(CHR⁶¹)_(s)NR³³R³⁴;        —(CH₂)_(m)(CHR⁶¹)_(s)OCONR³³R⁷⁵;        —(CH₂)_(m)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷;        —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂;        —(CH₂)_(o)(CHR⁶¹)_(s)SO₂R⁶²; or —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸;    -   R²⁶ is H; alkyl; alkenyl; —(CH₂)_(m)(CHR⁶¹)_(s)OR⁵⁵;        —(CH₂)_(m)(CHR⁶¹)_(s)SR⁵⁶; —(CH₂)_(m)(CHR⁶¹)_(s)NR³³R³⁴;        —(CH₂)_(m)(CHR⁶¹)_(s)OCONR³³R⁷⁵;        —(CH₂)_(m)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷;        —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂;        —(CH₂)_(o)(CHR⁶¹)_(s)SO₂R⁶²; or —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸; or    -   R²⁵ and R²⁶ taken together can form: —(CH₂)₂₋₆—;        —(CH₂)_(r)O(CH₂)_(r); —(CH₂)_(r)S(CH₂)_(r)—; or        —(CH₂)_(r)NR⁵⁷(CH₂)_(r)—;

R²⁷ is H; alkyl; alkenyl; —(CH₂)_(o)(CHR⁶¹)_(s)OR⁵⁵;—(CH₂)_(o)(CHR⁶¹)_(s)SR⁵⁸; —(CH₂)_(o)(CHR⁶¹)_(s)NR³³R³⁴;—(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷; —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹;—(CH₂)_(o)(CHR⁶¹)_(s)OCONR³³R⁷⁸; —(CH₂)_(o)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²;—(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁸⁰)₂; —(CH₂)_(o)(CHR⁶¹)_(s)SO₂R⁶²; or—(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸:

-   -   R²⁸ is alkyl; alkenyl; —(CH₂)_(o)(CHR⁶¹)_(s)—OR⁵⁸;        —(CH₂)_(o)(CHR⁶¹)_(s)SR⁵⁶; —(CH₂)_(o)(CHR⁶¹)_(s)NR³³R³⁴;        —(CH₂)_(o)(CHR⁶¹)_(s)OCONR³³R⁷⁵;        —(CH₂)_(o)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷;        —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁸; —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂;        —(CH₂)_(o)(CHR⁶¹)_(s)SO₂R⁸²; or —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸;    -   R²⁹ is alkyl; alkenyl; —(CH₂)_(o)(CHR⁶¹)_(s)OR⁸⁵;        —(CH₂)_(o)(CHR⁶¹)_(s)SR⁵⁶; —(CH₂)_(o)(CHR⁶¹)_(s)NR³³R³⁴;        —(CH₂)_(o)(CHR⁶¹)_(s)OCONR³³R⁷⁵;        —(CH₂)_(o)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷;        —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂;        —(CH₂)_(o)(CHR⁶¹)_(s)SO₂R⁶²; or —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸;    -   R³⁰ is H; alkyl; alkenyl; or aryl-lower alkyl;    -   R³¹ is H; alkyl; alkenyl; —(CH₂)_(p)(CHR⁶¹)_(s)OR⁵⁵;        —(CH₂)_(p)(CHR⁶¹)_(s)NR³³R³⁴; —(CH₂)_(p)(CHR⁶¹)_(s)OCONR³³R⁷⁵;        —(CH₂)_(p)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; (CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷;        —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; (CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂;        —(CH₂)_(o)(CHR⁶¹)_(s)SO₂R⁶²; or —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸;    -   R³² is H; lower alkyl; or aryl-lower alkyl;    -   R³³ is H; alkyl, alkenyl; —(CH₂)_(m)(CHR⁶¹)_(s)OR⁵⁵;        —(CH₂)_(m)(CHR⁶¹)_(s)NR³⁴R⁶³; —(CH₂)_(m)(CHR⁶¹)_(s)OCONR⁷⁵R⁸²;        —(CH₂)_(m)(CHR⁶¹)_(s)NR²⁰CONR⁷⁸R⁸²; —(CH₂)_(o)(CHR⁶¹)_(s)COR⁶⁴;        —(CH₂)_(o)(CHR⁶¹)_(s)—CONR⁵⁸R⁵⁸, —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂;        —(CH₂)_(o)(CHR⁶¹)_(s)SO₂R⁶²; or —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸;    -   R³⁴ is H; lower alkyl; aryl, or aryl-lower alkyl; or    -   R³³ and R³⁴ taken together can form: —(CH₂)₂₋₆—;        —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—;    -   R³⁵ is H; alkyl; alkenyl; —(CH₂)_(m)(CHR⁶¹)_(s)OR⁵⁵;        —(CH₂)_(m)(CHR⁶¹)_(s)NR³³R³⁴; —(CH₂)_(m)(CHR⁶¹)_(s)OCONR³³R⁷⁵;        —(CH₂)_(m)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(p)(CHR⁶¹)_(s)COOR⁵⁷;        —(CH₂)_(p)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; —(CH₂)_(p)(CHR⁶¹)_(s)PO(OR⁶⁰)₂;        —(CH₂)_(p)(CHR⁶¹)_(s)SO₂R⁶²; or —(CH₂)_(p)(CHR⁶¹)_(s)C₆H₄R⁸;    -   R³⁶ is H, alkyl; alkenyl; —(CH₂)_(o)(CHR⁶¹)_(s)OR⁵⁵;        —(CH₂)_(p)(CHR⁶¹)_(s)NR³³R³⁴; —(CH₂)_(p)(CHR⁶¹)_(s)OCONR³³R⁷⁵;        —(CH₂)_(p)(CHR⁶¹)_(s)NR²⁰CONR³³K⁸²; —(CH₂)_(p)(CHR⁶¹)_(s)COOR⁵⁷;        —(CH₂)_(p)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; —(CH²)_(p)(CHR⁶¹)_(s)PO(OR⁶⁰)₂;        —(CH₂)_(p)(CHR⁶¹)_(s)SO₂R⁶²; or —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸;    -   R³⁷ is H; F; Br; Cl; NO₂; CF₃; lower alkyl;        —(CH₂)_(p)(CHR⁶¹)_(s)OR⁶⁵; —(CH₂)_(p)(CHR⁶¹)_(s)NR³³R³⁴;        —(CH₂)_(p)(CHR⁶¹)_(s)OCONR³³R⁷⁵;        —(CH₂)_(p)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷;        —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂;        —(CH₂)_(o)(CHR⁶¹)_(s)SO₂R⁶²; or —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸;    -   R³⁸ is H; F; Br; Cl; NO₂; CF₃; alkyl; alkenyl;        —(CH₂)_(p)(CHR⁶¹)_(s)OR⁵⁵; —(CH₂)_(p)(CHR⁸¹)_(s)NR³³R³⁴;        —(CH₂)_(p)(CHR⁶¹)_(s)OCONR³³R⁷⁵;        —(CH₂)_(p)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷;        —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁶⁸R⁶⁹; —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂;        —(CH₂)_(o)(CHR⁶¹)_(s)SO₂R⁶²; or —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸;    -   R³⁹ is H; alkyl; alkenyl; or aryl-lower alkyl;    -   R⁴⁰ is H; alkyl; alkenyl; or aryl-lower alkyl;    -   R⁴¹ is H; F; Br; Cl; NO₂; CF₃; alkyl; alkenyl;        —(CH₂)_(p)(CHR⁶¹)_(s)OR⁵⁵; —(CH₂)_(p)(CHR⁶¹)_(s)NR³³R³⁴;        —(CH₂)_(p)(CHR⁶¹)_(s)OCONR³³R⁷⁵;        —(CH₂)_(p)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷;        —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂;        —(CH₂)_(o)(CHR⁶¹)_(s)SO₂R⁶²; or —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸;    -   R⁴² is H; F; Br; Cl; NO₂; CF₃; alkyl; alkenyl;        —(CH₂)_(p)(CHR⁶¹)_(s)OR⁵⁵; —(CH₂)_(p)(CHR⁶¹)_(s)NR³³R³⁴;        —(CH₂)_(p)(CHR⁶¹)_(s)OCONR³³R⁷⁵;        —(CH₂)_(p)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷;        —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂;        —(CH₂)_(o)(CHR⁶¹)_(s)SO₂R⁶²; —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸;    -   R⁴³ is H; alkyl; alkenyl; —(CH₂)_(m)(CHR⁶¹)_(s)OR⁵⁵;        —(CH₂)_(m)(CHR⁶¹)_(s)NR³³R³⁴; —(CH₂)_(m)(CHR⁶¹)_(s)OCONR³³R⁷⁵;        —(CH₂)_(m)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷;        —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂;        —(CH₂)_(o)(CHR⁶¹)_(s)SO₂R⁶²; or —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸;    -   R⁴⁴ is alkyl; alkenyl; —(CH₂)_(r)(CHR⁶¹)_(s)OR⁵⁵;        —(CH₂)_(r)(CHR⁶¹)_(s)SR⁵⁶; —(CH₂)_(r)(CHR⁶¹)_(s)NR³³R³⁴;        —(CH₂)_(r)(CHR⁶¹)_(s)OCONR³³R⁷⁵;        —(CH₂)_(r)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(r)(CHR⁶¹)_(s)COOR⁵⁷;        —(CH₂)_(r)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; —(CH₂)_(r)(CHR⁶¹)_(s)PO(OR⁶⁰)₂;        —(CH₂)_(r)(CHR⁶¹)_(s)SO₂R₆₂; or —(CH₂)_(r)(CHR⁶¹)_(s)C₆H₄R⁸;    -   R⁴⁵ is H; alkyl; alkenyl; —(CH₂)_(o)(CHR⁶¹)_(s)OR⁵⁵;        —(CH₂)_(o)(CHR⁶¹)_(s)SR⁵⁶; —(CH₂)_(o)(CHR⁶¹)_(s)NR³³R³⁴;        —(CH₂)_(o)(CHR⁶¹)_(s)OCONR³³R⁷⁵;        —(CH₂)_(o)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷;        —(CH₂)_(s) (CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; —(CH₂)_(s)(CHR⁶¹)_(s)PO(OR⁶⁰)₂;        —(CH₂)_(s)(CHR⁶¹)_(s)SO₂R⁶²; or —(CH₂)_(s)(CHR⁶¹)_(s)C₆H₄R⁸;    -   R⁴⁶ is H; alkyl; alkenyl; or —(CH₂)_(o)(CHR⁶¹)_(p)C₆H₄R⁸;    -   R⁴⁷ is H; alkyl; alkenyl; or —(CH₂)_(o)(CHR⁶¹)_(s)OR⁵⁵;    -   R⁴⁸ is H; lower alkyl; lower alkenyl; or aryl-lower alkyl;    -   R⁴⁹ is H; alkyl; alkenyl; —(CHR⁶¹)_(s)COOR⁵⁷;        (CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; —(CHR⁶¹)_(s)PO(OR⁶⁰)₂; —(CHR⁶¹)_(s)SOR⁶²;        or —(CHR⁶¹)_(s)C₆H₄R⁸;    -   R⁵⁰ is H; lower alkyl; or aryl-lower alkyl;    -   R⁵¹ is H; alkyl; alkenyl; —(CH₂)_(m)(CHR⁶¹)_(s)OR⁵⁵;        —(CH₂)_(m)(CHR⁶¹)_(s)SR⁵⁶; —(CH₂)_(m)(CHR⁶¹)_(s)NR³³R³⁴;        —(CH₂)_(m)(CHR⁶¹)_(s)OCONR³³R⁷⁵;        —(CH₂)_(m)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷;        —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; —(CH₂)_(o)(CHR⁶¹)_(p)PO(OR⁶⁰)₂;        —(CH₂)_(p)(CHR⁶¹)_(s)SO₂R⁶²; or —(CH₂)_(p)(CHR⁶¹)_(s)C₆H₄R⁸;    -   R⁵² is H; alkyl; alkenyl; —(CH₂)_(m)(CHR⁶¹)_(s)OR⁵⁵;        —(CH₂)_(m)(CHR⁶¹)_(s)SR⁵⁶; —(CH₂)_(m)(CHR⁶¹)_(s)NR³³R³⁴;        —(CH₂)_(m)(CHR⁶¹)_(s)OCONR³³R⁷⁵;        —(CH₂)_(m)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷;        —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; —(CH₂)_(o)(CHR⁶¹)_(p)PO(OR⁶⁰)₂;        —(CH₂)_(p)(CHR⁶¹)_(s)SO₂R⁶²; or —(CH₂)_(p)(CHR⁶¹)_(s)C₆H₄R⁸;    -   R⁵³ is H; alkyl; alkenyl; —(CH₂)_(m)(CHR⁶¹)_(s)OR⁵⁵;        —(CH₂)_(m)(CHR⁶¹)_(s)SR⁵⁶; —(CH₂)_(m)(CHR⁶¹)_(s)NR³³R³⁴;        —(CH₂)_(m)(CHR⁶¹)_(s)OCONR³³R⁷⁵;        —(CH₂)_(m)(CHR⁶¹)_(s)NR²⁸CONR³³R⁸²; —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷;        —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; —(CH₂)_(o)(CHR⁶¹)_(p)PO(OR⁶⁰)₂;        —(CH₂)_(p)(CHR⁶¹)_(s)SO₂R⁶²; or —(CH₂)_(p)(CHR⁶¹)_(s)C₆H₄R⁸;    -   R⁵⁴ is H; alkyl; alkenyl; —(CH₂)_(m)(CHR⁶¹)_(s)OR⁵⁵;        —(CH₂)_(m)(CHR⁶¹)_(s)NR³³R³⁴; —(CH₂)_(o)(CHR⁶¹)_(s)OCONR³³R⁷⁵;        —(CH₂)_(m)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(o)(CHR⁶¹)COOR⁵⁷;        —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; or —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸;    -   R⁵⁵ is H; lower alkyl; lower alkenyl; aryl-lower alkyl;        —(CH₂)_(m)(CHR⁶¹)₃OR⁵⁷; —(CH₂)_(o)(CHR⁶¹)_(s)NR³⁴R⁶³;        —(CH₂)_(m)(CHR⁶¹)_(s)OCONR⁷⁵R⁹²;        —(CH₂)_(m)(CHR⁶¹)_(s)NR²⁰NR⁷⁸R⁸²; —(CH₂)_(o)(CHR⁶¹)_(s)—COR⁶⁴;        —(CH₂)_(o)(CHR⁶¹)COOR⁵⁷; or —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹;    -   R⁵⁶ is H; lower alkyl; lower alkenyl; aryl-lower alkyl;        —(CH₂)_(m)(CHR⁶¹)_(s)OR⁵⁷; —(CH₂)_(m)(CHR⁶¹)_(s)NR³⁴R⁶³;        —(CH₂)_(m)(CHR⁶¹)_(s)OCONR⁷⁵R⁸²; —(CH₂)_(m)        (CHR⁶¹)_(s)NR²⁰CONR⁷⁹R⁸²; —(CH₂)_(o)(CHR⁶¹)_(s)—COR⁶⁴; or        —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹;    -   R⁵⁷ is H; lower alkyl; lower alkenyl; aryl lower alkyl; or        heteroaryl lower alkyl;    -   R⁵⁸ is H; lower alkyl; lower alkenyl; aryl; heteroaryl;        aryl-lower alkyl; or heteroaryl-lower alkyl;    -   R⁵⁹ is H; lower alkyl; lower alkenyl; aryl; heteroaryl;        aryl-lower alkyl; or heteroaryl-lower alkyl; or    -   R⁵⁸ and R⁵⁹ taken together can form: —(CH₂)₂₋₆—;        —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—;    -   R⁶⁰ is H; lower alkyl; lower alkenyl; aryl; or aryl-lower alkyl;    -   R⁶¹ is alkyl; alkenyl; aryl; heteroaryl; aryl-lower alkyl;        heteroaryl-lower alkyl; —(CH₂)_(p)OR⁵⁵; —(CH₂)_(p)NR³³R³⁴;        —(CH₂)_(p)OCONR⁷⁵R⁹²; —(CH₂)_(p)NR²⁰CONR⁷⁹R⁸²; —(CH₂)_(o)COOR³⁷;        —(CH₂)_(o)PO(OR⁶⁰)₂;    -   R⁶² is lower alkyl; lower alkenyl; aryl, heteroaryl; or        aryl-lower alkyl;    -   R⁶³ is H; lower alkyl; lower alkenyl; aryl, heteroaryl;        aryl-lower alkyl; heteroaryl-lower alkyl; —COR⁶⁴; —COOR⁵⁷;        —CONR⁵⁵R⁵⁹; —SO₂R⁶²; or —PO(OR⁶⁹)₂; or R³⁴ and R⁶³ taken        together can form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—;        or —(CH₂)₂NR⁵⁷(CH₂)₂—;    -   R⁶⁴ is H; lower alkyl; lower alkenyl; aryl; heteroaryl;        aryl-lower alkyl; heteroaryl-lower alkyl;        —(CH₂)_(p)(CHR⁶¹)_(s)OR⁶⁵; —(CH₂)_(p)(CHR⁶¹)_(s)SR⁶⁶;        —(CH₂)_(p)(CHR⁶¹)_(s)NR³⁴R⁶³; —(CH₂)_(P)(CHR⁶¹)_(s)OCONR⁷⁵R⁸²;        or —(CH₂)_(P)(CHR⁶¹)_(s)NR²⁰CONR⁷⁸R⁸²;    -   R⁶⁵ is H; lower alkyl; lower alkenyl; aryl, aryl-lower alkyl;        heteroaryl-lower alkyl; —COR⁵⁷; —COOR⁵⁷; or —CONR⁵⁸R⁵⁹;    -   R⁶⁶ is H; lower alkyl; lower alkenyl; aryl; aryl-lower alkyl;        heteroaryl-lower alkyl; or —CONR⁵⁸R⁵⁹;    -   R⁶⁷ is H; Cl; Br; F; NO₂; —NR³⁴COR⁵⁷; —CF₃; CN; —OCF₃; —OCHF₂;        —OR⁵⁷; —SR⁶²; lower alkyl; or lower alkenyl;    -   R⁶⁸ is H; Cl; Br; F; NO₂; —NR³⁴COR⁵⁷; —CF₃; CN; —OCF₃; —OCHF₂;        —OR⁵⁷; —SR⁶²; lower alkyl; or lower alkenyl;    -   R⁶⁹ is H; Cl; Br; F; NO₂; —NR³⁴COR⁵⁷; —CF₃; CN; —OCF₃; —OCHF₂;        —OR⁵⁷; —SR⁶²; lower alkyl; or lower alkenyl;    -   R⁷⁰ is H; Cl; Br; F; NO₂; —NR³⁴COR⁵⁷; —CF₃; CN; —OCF₃; —OCHF₂;        —OR⁵⁷; —SR⁶²; lower alkyl; or lower alkenyl;    -   R⁷¹ is lower alkyl; lower alkenyl; —(CH₂)_(p)(CHR⁶¹)_(s)OR⁷⁵;        —(CH₂)_(p)(CHR⁶¹)_(s)SR⁷⁵; —(CH₂)_(p)(CHR⁶¹)_(s)NR³³R³⁴;        —(CH₂)_(p)(CHR⁶¹)_(s)OCONR³³R⁷⁵;        —(CH₂)_(p)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁷⁵;        —(CH₂)_(p)CONR⁵⁸R⁵⁹; —(CH₂)_(p)PO(OR⁶²)₂; —(CH₂)_(p)SO₂R⁶²; or        —(CH₂)_(o)—C₆R⁶⁷R⁶⁸R⁶⁹R⁷⁰R⁷⁶;    -   R⁷² is alkyl; alkenyl; —(CH₂)_(p)(CHR⁶¹)_(s)OR⁸⁵; or        —(CH₂)_(p)(CHR⁶¹)_(s)SR⁸⁵;    -   R⁷³ is —(CH₂)_(o)R⁷⁷; —(CH₂)_(r)S(CH₂)_(o)R⁷⁷;        —(CH₂)_(r)S(CH₂)_(o)R⁷⁷; or —(CH₂)_(r)NR²⁰(CH₂)_(o)R⁷⁷;    -   R⁷⁴ is —(CH₂)_(p)NR⁷⁸R⁷⁹; —(CH₂)_(p)NR⁷⁷R⁸⁰;        —(CH₂)_(p)C(═NR⁸⁰)NR⁷⁸R⁷⁹; —(CH₂)_(p)C(═NOR⁵⁰)NR⁷⁸R⁷⁹;        —(CH₂)_(p)C(═NNR⁷⁸R⁷⁹)NR⁷⁸R⁷⁹; —(CH₂)_(p)NR⁸⁰C(═NR⁸⁰)NR⁷⁸R⁷⁹;        —(CH₂)_(p)N═C)NR⁷⁸R⁸⁰)NR⁷⁹R⁸⁰; —(CH₂)_(p)C₆H₄NR⁷⁸R⁷⁹;        —(CH₂)_(p)C₆H₄NR⁷⁷R⁸⁰; —(CH₂)_(p)C₆H₄C(═NR⁸⁰)NR⁷⁸R⁷⁹;        —(CH₂)_(p)C₆H₄C(═NOR⁵⁰)NR⁷⁸R⁷⁹;        —(CH₂)_(p)C₆H₄C(═NNR⁷⁸R⁷⁹)NR⁷⁸R⁷⁹;        —(CH₂)_(p)C₆H₄NR⁸⁰C(═NR⁸⁰)NR⁷⁸R⁷⁹;        —(CH₂)_(p)C₆H₄C(═NR⁷⁸R⁸⁰)NR⁷⁹R⁸⁰; —(CH₂)_(r)O(CH₂)_(m)NH⁷⁸H⁷⁹;        —(CH₂)_(r)O(CH₂)_(m)NR⁷⁷R⁸⁰;        —(CH₂)_(r)O(CH₂)_(p)C(═NR⁸⁰)NR⁷⁸R⁷⁹;        —(CH₂)_(r)O(CH₂)_(p)C(═—(CH₂)_(r)O(CH₂)_(p)C(═NNR⁷⁸R⁷⁹)NR⁷⁸R⁷⁹;        —(CH₂)_(r)O(CH₂)_(m)NR⁸⁰C(═NR⁸⁰)NR⁷⁸R⁷⁹;        —(CH₂)_(r)O(CH₂)_(m)N═C(NR⁷⁸R⁸⁰)NR⁷⁹R⁸⁰ ;        —(CH₂)_(r)O(CH₂)_(p)C₆H₄CNR⁷⁸R⁷⁹;        —(CH₂)_(r)O(CH₂)_(p)C₆H₄C(═NR⁸⁰)NR⁷⁸R⁷⁹;        —(CH₂)_(r)O(CH₂)_(p)C₆H₄C(═NOR⁵⁰)NR⁷⁸R⁷⁹;        —(CH₂)_(r)O(CH₂)_(p)C₆H₄C(═NNR⁷⁸R⁷⁹)NR⁷⁸R⁷⁹;        —(CH₂)_(r)O(CH₂)_(p)C₆H₄NR⁸⁰C(═NR⁸⁰)NR⁷⁸R⁷⁹;        —(CH₂)_(r)S(CH₂)_(m)NR⁷⁸R⁷⁹; —(CH₂)_(r)S(CH₂)_(m)NR⁷⁷R⁸⁰;        —(CH₂)_(r)S(CH₂)_(p)C(═NR⁸⁰)NR⁷⁸R⁷⁹;        —(CH₂)_(r)S(CH₂)_(p)C(═NOR⁵⁰)NR⁷⁸R⁷⁹;        —(CH₂)_(r)S(CH₂)_(p)C(═NNR⁷⁸R⁷⁹)NR⁷⁸R⁷⁹;        —(CH₂)_(r)S(CH₂)_(m)NR⁸⁰C(═NR⁸⁰)NR⁷⁸R⁷⁹;        —(CH₂)_(r)S(CH₂)_(m)N═C(NR⁷⁸R⁸⁰)NR⁷⁸R⁸⁰;        —(CH₂)_(r)S(CH₂)_(p)C₆H₄CNR⁷⁸R⁷⁹;        —(CH₂)_(r)S(CH₂)_(p)C₆H₄C(═NR⁸⁰)NR⁷⁸R⁷⁹;        —(CH₂)_(r)S(CH₂)_(p)C₆H₄C(═NOR⁵⁰)NR⁷⁸R⁷⁹;        —(CH₂)_(r)S(CH₂)_(p)C₆H₄C(═NNR⁷⁸R⁷⁹)NR⁷⁸R⁷⁹;        —(CH₂)_(r)S(CH₂)_(p)C₆H₄NR⁸⁰C(═NR⁸⁰)NR⁷⁸R⁷⁹;        —(CH₂)_(p)NR⁸⁰COR⁶⁴; —(CH₂)_(p)NR⁸⁰COR⁷⁷;        —(CH₂)_(p)NR⁸⁰CONR⁷⁸R⁷⁹; or —(CH₂)_(p)C₆H₄NR⁸⁰CONR⁷⁸R⁷⁹;    -   R⁷⁵ is lower alkyl; lower alkenyl; or aryl-lower alkyl; or    -   R³³ and R⁷⁵ taken together can form: —(CH₂)₂₋₆—:        —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; or    -   R⁷⁵ and R⁸² taken together can form: —(CH₂)₂₋₆—;        —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—;    -   R⁷⁶ is H; lower alkyl; lower alkenyl; aryl-lower alkyl;        —(CH₂)_(o)OR⁷²; —(CH₂)_(o)SR⁷²; —(CH₂)_(o)NR³³R³⁴;        —(CH₂)_(o)OCONR³³R⁷⁵; —(CH₂)_(o)NR²⁰CONR³³R⁸¹; —(CH₂)_(o)COOR⁷⁵;        —(CH₂)_(o)CONR⁵⁸R⁵⁹; —(CH₂)_(o)PO(OR⁶⁰)²; —(CH₂)_(p)SO₂R⁶²; or        —(CH₂)_(o)COR⁶⁴;    -   R⁷⁷ is —C₆R⁶⁷R⁶⁸R⁶⁹R⁷⁰R⁷⁶ with the proviso that at least two of        R⁶⁷, R⁶⁸, R⁶⁹ and R⁷⁰ are H; or a heteroaryl group of one of the        formulae

-   -   R⁷⁸ is H; lower alkyl; aryl; or aryl-lower alkyl; or    -   R⁷⁸ and R⁸² taken together can form: —(CH₂)₂₋₆—;        —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—;    -   R⁷⁹ is H; lower alkyl; aryl; or aryl-lower alkyl; or    -   R⁷⁸ and R⁷⁹, taken together, can be —(CH₂)₂₋₇—; —(CH₂)₂O(CH₂)₂—;        or —(CH₂)₂NR⁵⁷(CH₂)₂—;    -   R⁸⁰ is H; or lower alkyl;    -   R⁸¹ is H; lower alkyl; or aryl-lower alkyl;    -   R³³ and R⁸¹ taken together can form: —(CH₂)₂₋₆—:        —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—;    -   R⁸² is H; —CF₃; —OCF₃; —OCHF₂; lower alkyl; aryl; heteroaryl; or        aryl-lower alkyl;    -   R⁸³ is H; lower alkyl; aryl; or —NR⁷⁸R⁷⁹;    -   R⁸⁴ is —(CH₂)_(p)(CHR⁸¹)_(s)OH; —(CH₂)_(p)COOR⁸⁰;        —(CH₂)_(p)(CHR⁶¹)_(s)SH; —(CH₂)_(p)CONR⁷⁸R⁷⁹;        —(CH₂)_(p)NR⁸⁰CONR⁷⁸R⁷⁹; —(CH₂)_(p)C₆H₄CONR⁷⁸R⁷⁹; or        —(CH₂)_(p)C₆H₄NR⁸⁰CONR⁷⁸R⁷⁹;    -   R⁸⁵ is lower alkyl; or lower alkenyl;

m is 2-4; o is 0-4; p is 1-4; q is 0-2; r is 1 or 2; s is 0 or 1;

Z is a chain of 14 α-amino and/or α-hydroxy acid residues, the positionsof said amino and/or hydroxy acid residues in said chain being countedstarting from the N-terminal amino acid or O-terminal hydroxy acid,whereby these amino or hydroxy acid residues are, depending on theirposition in the chains, Gly, a Glycolic acid residue, Pro, -A-CO—, or ofone of the types

-   -   C: —NR²⁰CH(R⁷²)CO—;    -   D: —NR²⁰CH(R⁷³)CO—;    -   E: —NR²⁰CH(R⁷⁴)CO—;    -   F: —NR²⁰CH(R⁸⁹)CO—;    -   H: —NR²⁰—CH(CO—)—(CH₂)₄₋₇—CH(CO—)—NR²⁰—;        —NR²⁰—CH(CO—)—(CH₂)_(p)SS(CH₂)_(p)—CH(CO—)—NR²⁰—;        —NR²⁰—CH(CO—)—(—(CH₂)_(p)NR²⁰CO(CH₂)_(p)—CH(CO—)—NR²⁰—; or        —NR²⁰—CH(CO—)—(—(CH₂)_(p)NR²⁰CONR²⁰(CH₂)_(p)—CH(CO—)—NR²⁰—; and    -   L: —O—CH(R⁷¹)CO—; —O—CH(R⁷²)CO—; —O—CH(R⁷⁸)CO—; —O—CH(R⁷⁴)CO—;        or —OCH(R⁸⁴)CO—;        with the proviso that in said chain Z of 14 α-amino and/or        α-hydroxy acid residues the amino or hydroxy acid residues in        positions 1 to 14 are:    -   P1: of type C, type D, type F or of type L;    -   P2: of type D, type E, type F, or of type L;    -   P3: of type C, type D, type E, type F, type L, or Gly, or a        Glycolic acid residue;    -   P4: of type C, type D, type E or of type F;    -   P5: of type E, type F or of type L;    -   P6: of type C, type L, Gly or a Glycolic acid residue;    -   P7: of formula -A-CO—, Pro, Gly or a Glycolic acid residue;    -   P8: of formula A-CO—, type C, type D, type E, type F or of type        L;    -   P9: of type D or type E;    -   P10: of type C or type D;    -   P11: of type C, type D or type F;    -   P12: of type D, type F or of type L;    -   P13: of type C, type D, type E, type F or of type L; and    -   P14: of type C, type E, type F or of type L; or    -   P4 and P11, taken together, can form a group of type H;    -   at P5, P7 and P13 also D-isomers being possible;        and with the further proviso that the molecule contains at least        one but not more than 3 α-hydroxy acid residues; and        pharmaceutically acceptable salts thereof.

In accordance with the present invention these β-hairpin peptidomimeticscan be prepared by a process which comprises

-   -   (a) coupling an appropriately functionalized solid support with        an appropriately N-protected derivative of that amino acid or an        appropriately O-protected derivative of that hydroxy acid which        in the desired end-product is in positions 3, 5, 6, 7, 8 or 10,        any functional group which may be present in said N-protected        amino acid derivative or O-protected hydroxy acid derivative        being likewise appropriately protected;    -   (b) removing the N-protecting or O-protecting group from the        product thus obtained;    -   (c) coupling the product thus obtained with an appropriately        N-protected derivative of that amino acid or an appropriately        O-protected derivative of that hydroxy acid which in the desired        end-product is one position nearer the N-terminal amino acid        residue or O-terminal hydroxy acid residue, any functional group        which may be present in said N-protected amino acid derivative        or O-protected hydroxy acid derivative being likewise        appropriately protected;    -   (d) removing the N-protecting group or O-protecting group from        the product thus obtained;    -   (e) repeating steps (c) and (d) until the N-terminal amino acid        residue or O-terminal hydroxy acid residue has been introduced;    -   (f) coupling the product thus obtained with one of the compounds        of the general formulae

-   -   -   wherein

-   -   -   is as defined above and X is an N-protecting group and,            respectively, an O-protecting group; or, alternatively, if

-   -   -   is to be group (a1) or (a2) above,        -   (fa) coupling the product obtained in step (e) with an            appropriately N-protected derivative of an amino acid or an            appropriately O-protected derivative of a hydroxy acid of            the general formula

HOOC-B-H   III

or

HOOC-A-H   IV

-   -   -   -   wherein B and A are as defined above, any functional                group which may be present in said N-protected amino                acid derivative or O-protected hydroxy acid derivative                being likewise appropriately protected;

        -   (fb) removing the N-protecting group or O-protecting group            from the product thus obtained; and

        -   (fc) coupling the product thus obtained with an            appropriately N-protected derivative of an amino acid or an            appropriately O-protected derivative of a hydroxy acid of            the above general formula IV and, respectively, III, any            functional group which may be present in said N-protected            amino acid derivative or O-protected hydroxy acid derivative            being likewise appropriately protected;

    -   (g) removing the N-protecting group or O-protecting group from        the product obtained in step (f) or (fc);

    -   (h) coupling the product thus obtained with an appropriately        N-protected derivative of that amino acid or an appropriately        O-protected derivative of that hydroxy acid which in the desired        end-product is in position 14, any functional group which may be        present in said N-protected amino acid derivative or O-protected        hydroxy acid derivative being likewise appropriately protected;

    -   (i) removing the N-protecting group or O-protecting group from        the product thus obtained;

    -   (j) coupling the product thus obtained with an appropriately        N-protected derivative of that amino acid or an appropriately        O-protected derivative of that hydroxy acid which in the desired        end-product is one position farther away from position 14, any        functional group which may be present in said N-protected amino        acid derivative or O-protected hydroxy acid derivative being        likewise appropriately protected;

    -   (k) removing the N-protecting group or O-protecting group from        the product thus obtained;

    -   (l) repeating steps (j) and (k) until all amino acid or hydroxy        acid residues have been introduced;

    -   (m) if desired, selectively deprotecting one or several        protected functional group(s) present in the molecule and        appropriately substituting the reactive group(s) thus liberated;

    -   (n) if desired, forming an interstrand linkage between        side-chains of appropriate amino acid residues at positions P4        and P11;

    -   (o) detaching the product thus obtained from the solid support;

    -   (p) cyclizing the product cleaved from the solid support;

    -   (q) removing any protecting groups present on functional groups        of any members of the chain of amino acid and/or hydroxy acid        residues and, if desired, any protecting group(s) which may in        addition be present in the molecule; and

    -   (r) if desired, converting the product thus obtained into a        pharmaceutically acceptable salt or converting a        pharmaceutically acceptable, or unacceptable, salt thus obtained        into the corresponding free compound of formula Ia or Ib or into        a different, pharmaceutically acceptable, salt.

Alternatively, the peptidomimetics of the present invention can beprepared by

-   -   (a′) coupling an appropriately functionalized solid support with        one of the compounds of the general formulae

-   -   -   wherein

-   -   -   is as defined above and X is an N-protecting group or an            O-protecting group, or, alternatively, if

-   -   -   is to be group (a1) or (a2) above,        -   (a′a) coupling said appropriately functionalized solid            support with an appropriately N-protected derivative of an            amino acid or an appropriately O-protected derivative of a            hydroxy acid of the general formula

HOOC-B-H   III

or

HOOC-A-H   IV

-   -   -   -   wherein B and A are as defined above, any functional                group which may be present in said N-protected amino                acid derivative or O-protected hydroxy acid derivative                being likewise appropriately protected;

        -   (a′b) removing the N-protecting group or O-protecting group            from the product thus obtained; and

        -   (a′c) coupling the product thus obtained with an            appropriately N-protected derivative of an amino acid or an            appropriately O-protected derivative of a hydroxy acid of            the above general formula IV and, respectively, III, any            functional group which may be present in said N-protected            amino acid derivative or O-protected hydroxy acid derivative            being likewise appropriately protected;

    -   (b′) removing the N-protecting group or O-protecting group from        the product obtained in step (a′) or (a′c)

    -   (c′) coupling the product thus obtained with an appropriately        N-protected derivative of that amino acid or an appropriately        O-protected derivative of that hydroxy acid which in the desired        end-product is in position 14, any functional group which may be        present in said N-protected amino acid derivative or O-protected        hydroxy acid derivative being likewise appropriately protected;

    -   (d′) removing the N-protecting group or O-protecting group from        the product thus obtained;

    -   (e′) coupling the product thus obtained with an appropriately        N-protected derivative of that amino acid or an appropriately        O-protected derivative of that hydroxy acid which in the desired        end-product is one position farther away from position 14, any        functional group which may be present in said N-protected amino        acid derivative or O-protected hydroxy acid derivative being        likewise appropriately protected;

    -   (f′) removing the N-protecting group or O-protecting group from        the product thus obtained;

    -   (g′) repeating steps (e′) and (f′) until all amino acid or        hydroxy acid residues have been introduced;

    -   (h′) if desired, selectively deprotecting one or several        protected functional group(s) present in the molecule and        appropriately substituting the reactive group(s) thus liberated;

    -   (i′) if desired forming an interstrand linkage between        side-chains of appropriate amino acid residues at positions P4        and P11;

    -   (j′) detaching the product thus obtained from the solid support;

    -   (k′) cyclizing the product cleaved from the solid support;

    -   (l′) removing any protecting groups present on functional groups        of any members of the chain of amino acid and/or hydroxy acid        residues and, if desired, any protecting group(s) which may in        addition be present in the molecule; and

    -   (m′) if desired, converting the product thus obtained into a        pharmaceutically acceptable salt or converting a        pharmaceutically acceptable, or unacceptable, salt thus obtained        into the corresponding free compound of formula Ia or Ib or into        a different, pharmaceutically acceptable, salt.

According to a further alternative, peptidomimetics of the presentinvention wherein

-   -   is to be group (a1) or (a2) above, can be prepared by        -   (a″a) coupling an appropriately functionalized solid support            with an appropriately N-protected derivative of an amino            acid or an appropriately O-protected derivative of a hydroxy            acid of the general formula

HOOC-A-H   IV

or

HOOC-B-H   III

-   -   -   -   wherein A and B are as defined above, any functional                group which may be present in said N-protected amino                acid derivative or O-protected hydroxy acid derivative                being likewise appropriately protected;

        -   (a″b) removing the N-protecting group or O-protecting group            from the product thus obtained;

    -   (b″) coupling the product thus obtained with an appropriately        N-protected derivative of that amino acid or an appropriately        O-protected derivative of that hydroxy acid which in the desired        end-product is in position 14, any functional group which may be        present in said N-protected amino acid derivative or O-protected        hydroxy acid derivative being likewise appropriately protected;

    -   (c″) removing the N-protecting group or O-protecting group from        the product thus obtained;

    -   (d″) coupling the product thus obtained with an appropriately        N-protected derivative of that amino acid or an appropriately        O-protected derivative of that hydroxy acid which in the desired        end-product is one position farther away from position 14, any        functional group which may be present in said N-protected amino        acid derivative or O-protected hydroxy acid derivative being        likewise appropriately protected;

    -   (e″) removing the N-protecting group or O-protecting group from        the product thus obtained;

    -   (f″) repeating steps (d″) and (e″) until all amino acid or        hydroxy acid residues of the chain Z have been introduced;

    -   (g″)coupling the product thus obtained with an appropriately        N-protected derivative of an amino acid or an appropriately        O-protected derivative of a hydroxy acid of the above general        formula III and, respectively, IV, any functional group which        may be present in said N-protected amino acid derivative or        O-protected hydroxy acid derivative being likewise appropriately        protected;

    -   (h″)removing the N-protecting group or O-protecting group from        the product obtained in step ((g″)

    -   (i″) if desired, selectively deprotecting one or several        protected functional group(s) present in the molecule and        appropriately substituting the reactive group(s) thus liberated;

    -   (j″) if desired forming an interstrand linkage between        side-chains of appropriate amino acid residues at positions P4        and P11;

    -   (k″) detaching the product thus obtained from the solid support;

    -   (l″) cyclizing the product cleaved from the solid support;

    -   (m″) removing any protecting groups present on functional groups        of any members of the chain of amino acid and/or hydroxy acid        residues and, if desired, any protecting group(s) which may in        addition be present in the molecule; and

    -   (n″) if desired, converting the product thus obtained into a        pharmaceutically acceptable salt or converting a        pharmaceutically acceptable, or unacceptable, salt thus obtained        into the corresponding free compound of formula Ia or Ib or into        a different, pharmaceutically acceptable, salt.

The peptidomimetics of the present invention can also be enantiomers ofthe compounds of formula Ia or Ib. These enantiomers can be prepared bya modification of the above processes in which enantiomers of all chiralstarting materials are used.

As used in this description, the term “alkyl”, taken alone or incombinations, designates saturated, straight-chain or branchedhydrocarbon radicals having up to 24, preferably up to 12, carbon atoms.Similarly, the term “alkenyl” designates straight chain or branchedhydrocarbon radicals having up to 24, preferably up to 12, carbon atomsand containing at least one or, depending on the chain length, up tofour olefinic double bonds. The term “lower” designates radicals andcompounds having up to 6 carbon atoms. Thus, for example, the term“lower alkyl” designates saturated, straight-chain, or branchedhydrocarbon radicals having up to 6 carbon atoms, such as methyl, ethyl,n-propyl, isopropyl, n-butyl, sec.-butyl, isobutyl, tert.-butyl, and thelike. Similarly, the term “lower cycloalkyl” designates saturated cyclichydrocarbon radicals having up to 6 carbon atoms, such as cyclopentyl,cyclohexyl and the like. The term “aryl” designates aromatic carbocyclichydrocarbon radicals containing one or two six-membered rings, such asphenyl or naphthyl, which may be substituted by up to three substituentssuch as Br, Cl, F, CF₃, NO₂, lower alkyl or lower alkenyl. The term“heteroaryl” designates aromatic heterocyclic radicals containing one ortwo five- and/or six-membered rings, at least one of them containing upto three heteroatoms selected from the group consisting of O, S and Nand said ring(s) being optionally substituted; representative examplesof such optionally substituted heteroaryl radicals are indicatedhereinabove in connection with the definition of R⁷⁷.

The structural element -A-CO— designates amino acid building blockswhich in combination with the structural element -B-CO— form templates(a1) and (a2). Templates (a) through (p) constitute building blockswhich have an N- or O-terminus and a C-terminus oriented in space insuch a way that the distance between those two groups may lie between4.0-5.5 A. A peptide or depsipeptide chain Z is linked to the C-terminusand the N- or O-terminus of the templates (a) through (p) via thecorresponding N- or O- and C-termini so that the template and the chainform a cyclic structure such as that depicted in formulae Ia or Ib. In acase as here where the distance between the N- or O- and C- termini ofthe template lies between 4.0-5.5 A the template will induce the H-bondnetwork necessary for the formation of a β-hairpin conformation in thepeptide or depsipeptide chain Z. Thus template and peptide ordepsipeptide chain form a β-hairpin mimetic.

The β-hairpin conformation is highly relevant for the CXCR4 antagonizingactivity of the β-hairpin mimetics of the present invention. Theβ-hairpin stabilizing conformational properties of the templates (a)through (p) play a key role not only for the selective antagonizingactivity but also for the synthesis process defined hereinabove, asincorporation of the templates (a) through (p) or part of the templates(a) at the beginning or near the middle of the linear protected peptideor depsipeptide precursors enhances cyclization yields significantly.

Building blocks A1-A69 and A105 belong to a class of amino acids whereinthe N-terminus is a secondary amine forming part of a ring. Among thegenetically encoded amino acids only proline falls into this class. Theconfiguration of building block A1 through A69 and A105 is (D), and theyare combined with a building block -B-CO— of (L)-configuration.Preferred combinations for templates (a1) are -^(D)A1-CO-^(L)B-CO— to-^(D)A69-CO-^(L)B-CO— and -^(D)A105-CO-^(L)B-CO—. Thus, for example,^(D)Pro-^(L)Pro constitutes the prototype of templates (a1). Lesspreferred, but possible are combinations -^(L)B-CO-^(D)A1-CO— to^(D)A69-CO— and -^(D)A105-CO-¹B-CO-forming templates (a2). Thus, forexample, ^(L)Pro-^(D)Pro constitutes the prototype of template (a2).

It will be appreciated that building blocks -A1-CO— to -A69-CO— andA105-CO— in which A has (D)-configuration, are carrying a group R¹ atthe β-position to the N-terminus. The preferred values for R¹ are H andlower alkyl with the most preferred values for R^(l) being H and methyl.It will be recognized by those skilled in the art, that A1-A69 and A105are shown in (D)-configuration which, for R¹ being H and methyl,corresponds to the (R)-configuration. Depending on the priority of othervalues for R¹ according to the Cahn, Ingold and Prelog rules, thisconfiguration may also have to be expressed as (S).

In addition to R¹ building blocks -A1-CO— to -A69-CO— and A105-CO— cancarry an additional substituent designated as R² to R¹⁷. This additionalsubstituent can be H, and if it is other than H, it is preferably asmall to medium-sized aliphatic or aromatic group. Examples of preferredvalues for R² to R¹⁷ are:

-   -   R²: H; lower alkyl; lower alkenyl; —(CH₂)_(m)OR⁵⁵ (where R⁵⁵:        lower alkyl; or lower alkenyl); —(CH₂)_(m)SR⁵⁶ (where R⁵⁶: lower        alkyl; or lower alkenyl); —(CH₂)_(m)NR³³R³⁴ (where R³³: lower        alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; R³³ and R³⁴        taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂— where R⁵⁷: H; or lower        alkyl); —(CH₂)_(m)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; or        lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together        form: —(CH₂)₂₋₆—); —(CH₂)₂O(CH₂)—(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(m)NR²⁰CONR³³R⁸¹ (where R²⁰: H; or lower lower alkyl;        R³³: H; or lower alkyl; or lower alkenyl; R⁸¹: H; or lower        alkyl; or R³³ and R⁸¹ taken together form: —(CH₂)₂₋₆—;        —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where        R⁵⁷: H; or lower alkyl); —(CH₂)_(o)N(R²⁰)COR⁶⁴ (where: R²⁰: H;        or lower alkyl; R⁶⁴: lower alkyl; or lower alkenyl);        —(CH₂)_(l)COOR⁵⁷ (where R⁵⁷: lower alkyl; or lower alkenyl);        —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl; or lower alkenyl;        and R⁵⁹: H; or lower alkyl; or R⁵⁸ and R⁵⁹ taken together form:        —(CH₂)₂₋₆—; —(CH₂)₂O(OH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰: H; lower alkyl; or lower        alkenyl); —(CH₂)_(o)SO₂R⁶² (where R⁶²: lower alkyl; or lower        alkenyl); —(CH₂)_(q)C₆H₄R⁸ (where R³: H; F; Cl; CF₃; lower        alkyl; lower alkenyl; or lower al koxy); or —(CH₂)_(q)CHN₄R⁸.    -   R³: H; lower alkyl; lower alkenyl; —(CH₂)_(m)OR⁵⁵ (where R⁵⁵:        lower alkyl; or lower alkenyl); —(CH₂)_(m)SR⁵⁶ (where R⁵⁶: lower        alkyl; or lower alkenyl); —(CH₂)_(m)NR³³R³⁴ (where R³³: lower        alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴        taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl); —(CH₂)_(m)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; or        lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together        form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(m)NR²⁰CONR³³R⁸¹ (where R²⁰: H; or lower lower alkyl;        R³³: H; or lower alkyl; or lower alkenyl; R⁸¹: H; or lower        alkyl; or R³³ and R⁸¹ taken together form: —(CH₂)₂₋₆—;        —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where        R⁵⁷: H; or lower alkyl); —(CH₂)_(o)N(R²⁰)COR⁶⁴ (where: R²⁰: H;        or lower alkyl; R⁶⁴: lower alkyl; or lower alkenyl);        —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷: lower alkyl; or lower alkenyl);        —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl; or lower alkenyl;        and R⁵⁹: H; lower alkyl; or R⁵⁸ and R⁵⁹ taken together form:        —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(p)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or lower alkenyl);        —(CH₂)_(o)SO₂R⁶² (where R⁶²: lower alkyl; or lower alkenyl); or        —(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower alkyl; lower        alkenyl; or lower alkoxy).    -   R⁴: H; lower alkyl; lower alkenyl; —(CH₂)_(m)OR⁵⁵ (where R⁵⁵:        lower alkyl; or lower alkenyl); —(CH₂)_(m)SR⁵⁶ (where R⁵⁶: lower        alkyl; or lower alkenyl); —(CH₂)_(m)NR³³R³⁴ (where R³³: lower        alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴        taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl); —(CH₂)_(m)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; or        lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together        form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(m)NR²⁰CONR³³R⁸¹ (where R²⁰: H; or lower lower alkyl;        R³³: H; or lower alkyl; or lower alkenyl; R⁸¹: H; or lower        alkyl; or R³³ and R⁸¹ taken together form: —(CH₂)₂₋₆—;        —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where        R⁵⁷: H; or lower alkyl); —(CH₂)_(m)N(R²⁰)COR⁶⁴ (where: R²⁰: H;        or lower alkyl; R⁶⁴: lower alkyl; or lower alkenyl);        —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷: lower alkyl; or lower alkenyl);        —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁶: lower alkyl; or lower alkenyl;        and R⁵⁹: H; or lower alkyl; or R⁵⁸ and R⁵⁹ taken together form:        —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or lower alkenyl);        —(CH₂)_(o)SO₂R⁶² (where R⁶²: lower alkyl; or lower alkenyl); or        —(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower alkyl; lower        alkenyl; or lower alkoxy).    -   R⁵: lower alkyl; lower alkenyl; —(CH₂)_(o)OR⁵⁵ (where R⁵⁵: lower        alkyl; or lower alkenyl); —(CH₂)_(o)SR⁵⁶ (where R⁵⁶: lower        alkyl; or lower alkenyl); —(CH₂)_(o)NR³³R³⁴ (where R³³: lower        alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴        taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl); —(CH₂)_(o)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; or        lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together        form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(o)NR²⁰CONR³³R⁸¹ (where R²⁰: H; or lower lower alkyl;        R³³: H; or lower alkyl; or lower alkenyl; R⁸¹: H; or lower        alkyl; or R³³ and R⁸¹ taken together form: —(CH₂)₂₋₆—; —(CH₂)₂        ^(o)(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷:        H; or lower alkyl); —(CH₂)_(o)N(R²⁰)COR⁶⁴ (where: R²⁰: H; or        lower alkyl; R⁶⁴: alkyl; alkenyl; aryl; and aryl-lower alkyl;        heteroaryl-lower alkyl); —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷: lower        alkyl; or lower alkenyl); —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower        alkyl; or lower alkenyl; and R⁵⁹: H; or lower alkyl; or R⁵⁸ and        R⁵⁹ taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl); —(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or lower        alkenyl); —(CH₂)_(o)SO₂R⁶² (where R⁶²: lower alkyl; or lower        alkenyl); or —(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower        alkyl; lower alkenyl; or lower alkoxy).    -   R⁶: H; lower alkyl; lower alkenyl; —(CH₂)_(o)OR⁵⁵ (where R⁵⁵:        lower alkyl; or lower alkenyl); —(CH₂)_(o)SR⁵⁶ (where R⁵⁶: lower        alkyl; or lower alkenyl); —(CH₂)_(o)NR³³R³⁴ (where R³³: lower        alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴        taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl); —(CH₂)_(o)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; or        lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together        form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(o)NR²⁰CONR³³K⁸¹ (where R²⁰: H; or lower lower alkyl;        R³³: H; or lower alkyl; or lower alkenyl; R⁸¹: H; or lower        alkyl; or R³³ and R⁸¹ taken together form: —(CH₂)₂₋₆—;        —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where        R⁵⁷: H; or lower alkyl); —(CH₂)_(o)N(R²⁰)COR⁶⁴ (where: R²⁰: H;        or lower alkyl; R⁶⁴: lower alkyl; or lower alkenyl);        —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷: lower alkyl; or lower alkenyl);        —(CH₂)_(o)CONR⁵⁵R⁵⁹ (where R⁵⁸: lower alkyl; or lower alkenyl;        and R⁵⁹: H; or lower alkyl; or R⁵⁸ and R⁵⁹ taken together form:        —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(o)PO(OR⁶⁶)₂ (where R⁶⁰: lower alkyl; or lower alkenyl);        —(CH₂)_(o)SO₂R⁶² (where R⁶²: lower alkyl; or lower alkenyl); or        —(CH₂)_(q)C₆H₄R⁵ (where R⁸: H; F; Cl; CF₃; lower alkyl; lower        alkenyl; or lower alkoxy).    -   R⁷: lower alkyl; lower alkenyl; —(CH₂)_(q)OR⁵⁵ (where R⁵⁵: lower        alkyl; or lower alkenyl); —(CH₂)_(q)SR⁵⁶ (where R⁵⁶ lower alkyl;        or lower alkenyl); —(CH₂)_(q)NR³³R³⁴ (where R³³: lower alkyl; or        lower alkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴ taken        together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(q)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; or lower        alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together form:        —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(q)NR²⁰CONR³³R⁸¹ (where R²⁰: H; or lower lower alkyl;        R³³: H; or lower alkyl; or lower alkenyl; R⁸¹: H; or lower        alkyl; or R³³ and R⁵¹ taken together form: —(CH₂)₂₋₆—;        —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where        R⁵⁷: H; or lower alkyl); —(CH₂)_(q)N(R²⁰)COR⁶⁴ (where: R²⁰: H;        or lower alkyl; R⁶⁴: lower alkyl; or lower alkenyl);        —(CH₂)_(r)COOR⁵⁷ (where R⁵⁷: lower alkyl; or lower alkenyl);        —(CH₂)_(q)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl; or lower alkenyl;        and R⁵⁹: H; or lower alkyl; or R⁵⁸ and R⁵⁹ taken together form:        —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(r)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or lower alkenyl);        —(CH₂)_(r)SO₂R⁶² (where R⁶²: lower alkyl; or lower alkenyl); or        —(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower alkyl; lower        alkenyl; or lower alkoxy).    -   R⁸: H; F; Cl; CF₃; lower alkyl; lower alkenyl; —(CH₂)_(o)OR⁵⁵        (where R⁵⁵: lower alkyl; or lower alkenyl); —(CH₂)_(o)SR⁵⁶        (where R⁵⁶: lower alkyl; or lower alkenyl); —(CH₂)_(o)NR³³R³⁴        (where R³³: lower alkyl; or lower alkenyl; R³⁴: H; or lower        alkyl; or R³³ and R³⁴ taken together form: —(CH₂)₂₋₆—;        —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where        R⁵⁷: H; or lower alkyl); —(CH₂)_(o)OCONR³³R⁷⁵ (where R³³: H; or        lower alkyl; or lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵        taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl); —(CH₂)_(o)NR²⁰CONR³³R⁸¹ (where R²⁰: H; or lower lower        alkyl; R³³: H; or lower alkyl; or lower alkenyl; R⁸¹: H; or        lower alkyl; or R³³ and R⁸¹ taken together form: —(CH₂)₂₋₆—;        —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where        R⁵⁷: H; or lower alkyl); —(CH₂)_(o)N(R²⁰)COR⁶⁴ (where: R²⁰: H;        or lower alkyl; R⁶⁴: lower alkyl; or lower alkenyl);        —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷ : lower alkyl; or lower alkenyl);        —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl; or lower alkenyl;        and R⁵⁹: H; or lower alkyl; or R⁵⁸ and R⁵⁹ taken together form:        —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or lower alkenyl);        —(CH₂)_(o)SO₂R⁶² (where R⁶²: lower alkyl; or lower alkenyl); or        —(CH₂)_(q)C₆H₄R⁸ (where R⁸ : H; F; Cl; CF₃; lower alkyl; lower        alkenyl; or lower alkoxy).    -   R⁹: lower alkyl; lower alkenyl; —(CH₂)_(o)OR⁵⁵ (where R⁵⁵: lower        alkyl; or lower alkenyl); —(CH₂)_(o)SR⁵⁶ (where R⁵⁶: lower        alkyl; or lower alkenyl); —(CH₂)_(o)NR³³R³⁴ (where R³³: lower        alkyl; or lower alkenyl; R³⁹: H; or lower alkyl; or R³³ and R³⁴        taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl); —(CH₂)_(o)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; or        lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together        form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(m)NR²⁰CONR³³R⁸¹ (where R²⁰: H; or lower lower alkyl;        R³³: H; or lower alkyl; or lower alkenyl; R⁸¹: H; or lower        alkyl; or R³³ and R⁸¹ taken together form: —(CH₂)₂₋₆—;        —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where        R⁵⁷: H; or lower alkyl); —(CH₂)_(o)N(R²⁰)COR⁶⁴ (where: R²⁰: H;        or lower alkyl; R⁶⁹: lower alkyl; or lower alkenyl);        —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷: lower alkyl; or lower alkenyl);        —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl; or lower alkenyl;        and R⁵⁹: H; or lower alkyl; or R⁵⁸ and R⁵⁹ taken together form:        —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or lower alkenyl);        —(CH₂)_(o)SO₂R⁶² (where R⁶²: lower alkyl; or lower alkenyl); or        —(CH₂) ,C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower alkyl; lower        alkenyl; or lower alkoxy).    -   R¹⁰: lower alkyl; lower alkenyl; —(CH₂)_(o)OR⁵⁵ (where R⁵⁵:        lower alkyl; or lower alkenyl); —(CH₂)_(o)SR⁵⁶ (where R⁵⁶: lower        alkyl; or lower alkenyl); —(CH₂)_(o)NR³³R³⁴ (where R³³: lower        alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴        taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl); —(CH₂)_(o)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; or        lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together        form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(o)NR²⁰CONR³³R⁸¹ (where R²⁰: H; or lower lower alkyl;        R³³: H; or lower alkyl; or lower alkenyl; R⁸¹: H; or lower        alkyl; or R³³ and R⁸¹ taken together form: —(CH₂)₂₋₆—;        —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where        R⁵⁷: H; or lower alkyl); —(CH₂)_(o)N(R²⁰)COR⁶⁴ (where: R²⁰: H;        or lower alkyl; R⁶⁴: lower alkyl; or lower alkenyl);        —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷: lower alkyl; or lower alkenyl);        —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl; or lower alkenyl;        and R⁵⁹: H; lower alkyl; or R⁵⁸ and R⁵⁹ taken together form:        —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)^(o)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or lower alkenyl);        —(CH₂)_(o)SO₂R⁶² (where R⁶²: lower alkyl; or lower alkenyl); or        —(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower alkyl; lower        alkenyl; or lower alkoxy).    -   R¹¹: H; lower alkyl; lower alkenyl; —(CH₂)_(m)OR⁵⁵ (where R⁵⁵:        lower alkyl; or lower alkenyl); —(CH₂)_(m)SR⁵⁶ (where R⁵⁶: lower        alkyl; or lower alkenyl); —(CH₂)_(m)NR³³R³⁴ (where R³³: lower        alkyl; or lower alkenyl; R³⁹: H; or lower alkyl; or R³³ and R³⁴        taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl); —(CH₂)_(m)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; or        lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together        form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(m)NR²⁰CONR³³R⁸¹ (where R²⁰: H; or lower lower alkyl;        R³³: H; or lower alkyl; or lower alkenyl; R⁸¹: H; or lower        alkyl; or R³³ and R⁸¹ taken together form: —(CH₂)₂₋₆—;        —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where        R⁵⁷: H; or lower alkyl); —(CH₂)_(o)N(R²⁰)COR⁶⁴ (where: R²⁰: H;        or lower alkyl; R⁶⁴: lower alkyl; or lower alkenyl);        —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷: lower alkyl; or lower alkenyl);        —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl; or lower alkenyl;        and R⁵⁹: H; lower alkyl; or R⁵⁸ and R⁵⁹ taken together form:        —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(o)PO(OR⁶⁶)₂ (where R⁶⁰: lower alkyl; or lower alkenyl);        —(CH₂)_(o)SO₂R⁶² (where R⁶²: lower alkyl; or lower alkenyl); or        —(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower alkyl; lower        alkenyl; or lower alkoxy).    -   R¹²: H; lower alkyl; lower alkenyl; —(CH₂)_(m)OR⁵⁵ (where R⁵⁵:        lower alkyl; or lower alkenyl); —(CH₂)_(m)SR⁵⁶ (where R⁵⁶: lower        alkyl; or lower alkenyl); —(CH₂)_(m)NR³³R³⁴ (where R³³: lower        alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴        taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl); —(CH₂)_(m)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; or        lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵taken together        form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(m)NR²⁶CONR³³R⁸¹ (where R²⁰: H; or lower lower alkyl;        R³³: H; or lower alkyl; or lower alkenyl; R⁸¹: H; or lower        alkyl; or R³³ and R⁸¹ taken together form: —(CH₂)₂₋₆—;        —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where        R⁵⁷: H; or lower alkyl); —(CH₂)_(m)N(R²⁰)COR⁶⁴ (where: R²⁰: H;        or lower alkyl; R⁶⁴: lower alkyl; or lower alkenyl);        —(CH₂)_(r)COOR⁵⁷ (where R⁵⁷: lower alkyl; or lower alkenyl);        —(CH₂)_(r)CONR⁵⁸R⁵⁹ (where R⁵⁶: lower alkyl; or lower alkenyl;        and R⁵⁹: H; or lower alkyl; or R⁵⁸ and R⁵⁹ taken together form:        —(CH₂)₂₋₆—: —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(r)PO(OP⁶⁰)₂ (where R⁶⁰: lower alkyl; or lower alkenyl);        —(CH₂)_(o)SO₂R⁶² (where R⁶²: lower alkyl; or lower alkenyl); or        —(CH₂)_(o)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower alkyl; lower        alkenyl; or lower alkoxy).    -   R¹³: lower alkyl; lower alkenyl; —(CH₂)_(q)OR⁵⁵ (where R⁵⁵:        lower alkyl; or lower alkenyl); —(CH₂)_(q)SR⁵⁶ (where R⁵⁶: lower        alkyl; or lower alkenyl); —(CH₂)_(q)NR³³R³⁴ (where R³³: lower        alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴        taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl); —(CH₂)_(q)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; or        lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together        form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(q)NR²⁰CONR³³R⁸¹ (where R²⁰: H; or lower lower alkyl;        R³³: H; or lower alkyl; or lower alkenyl; R⁸¹: H; or lower        alkyl; or R³³ and R⁸¹ taken together form: —(CH₂)₂₋₆—;        —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where        R⁵⁷: H; or lower alkyl); —(CH₂)_(q)N(R²⁰)COR₆₄ (where: R²⁰: H;        or lower alkyl; R⁶⁴: lower alkyl; or lower alkenyl);        —(CH₂)_(r)COO⁵⁷ (where R⁵⁷: lower alkyl; or lower alkenyl);        —(CH₂)_(q)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl; or lower alkenyl;        and R⁵⁹: H; or lower alkyl; or R⁵⁸ and R⁵⁹ taken together form:        —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(r)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or lower alkenyl);        —(CH₂)_(r)SO₂R⁶² (where R⁶²: lower alkyl; or lower alkenyl); or        —(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower alkyl; lower        alkenyl; or lower alkoxy).    -   R¹⁴: H; lower alkyl; lower alkenyl; —(CH₂)_(m)OR⁵⁵ (where R⁵⁵:        lower alkyl; or lower alkenyl); —(CH₂)_(m)SR⁵⁶ (where R⁵⁶: lower        alkyl; or lower alkenyl); —(CH₂)_(m)NR³³R³⁴ (where R³³: lower        alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴        taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl); —(CH₂)_(m)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; or        lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together        form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(m)NR²⁰CONR³³R⁸¹ (where R²⁰: H; or lower lower alkyl;        R³³: H; or lower alkyl; or lower alkenyl; R⁸¹: H; or lower        alkyl; or R³³ and R⁸¹ taken together form: —(CH₂)₂₋₆—;        —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where        R⁵⁷: H; or lower alkyl); —(CH₂)_(m)N(R²⁰)COR⁶⁴ (where: R²⁰: H;        lower alkyl; R⁶⁴: lower alkyl; or lower alkenyl);        —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷: lower alkyl; or lower alkenyl);        —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl; or lower alkenyl;        and R⁵⁹: H; or lower alkyl; or R⁵⁸ and R⁵⁹ taken together form:        —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or lower alkenyl);        —(CH₂)_(o)SO₂R⁶² (where R⁶²: lower alkyl; or lower alkenyl);        —(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower alkyl; lower        alkenyl; or lower alkoxy).    -   R¹⁵: lower alkyl; lower alkenyl; —(CH₂)_(o)OR⁵⁵ (where R⁵⁵:        lower alkyl; or lower alkenyl); —(CH₂)_(o)SR⁵⁶ (where R⁵⁶: lower        alkyl; or lower alkenyl); —(CH₂)_(o)NR³³R³⁴ (where R³³: lower        alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴        taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂        ₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(o)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; or lower        alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together form:        —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(o)NR²⁰CONR³³R⁸¹ (where R²⁰: H; or lower lower alkyl;        R³³: H; or lower alkyl; or lower alkenyl; R⁸¹: H; or lower        alkyl; or R³³ and R⁸¹ taken together form: —(CH₂)₂₋₆—; —(CH₂        ₂O(CH₂)₂—; —(CH₂ ₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H;        or lower alkyl); —(CH₂)_(o)N(R)²⁰COR⁶⁴ (where: R²⁰: H; or lower        alkyl; R⁶⁴: lower alkyl; or lower alkenyl); particularly        favoured being —NR²⁰CO-lower alkyl (R²⁰: H; or lower alkyl);        —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷: lower alkyl; or lower alkenyl);        —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl, or lower alkenyl;        and R⁵⁹: H; lower alkyl; or R⁵⁸ and R⁵⁹ taken together form:        —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or lower alkenyl);        —(CH₂)_(o)SO₂R⁶² (where R⁶²: lower alkyl; or lower alkenyl); or        —(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower alkyl; lower        alkenyl; or lower alkoxy).    -   R¹⁶: lower alkyl; lower alkenyl; —(CH₂)_(o)OR⁵⁵ (where R⁵⁵:        lower alkyl; or lower alkenyl); —(CH₂)_(o)SR⁶⁶ (where R⁵⁶: lower        alkyl; or lower alkenyl); —(CH₂)_(o)NR³³R³⁴ (where R³³: lower        alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴        taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl); —(CH₂)_(o)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; or        lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together        form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(o)NR²⁰CONR³³R⁸¹ (where R²⁰: H; or lower lower alkyl;        R³³: H; or lower alkyl; or lower alkenyl; R⁸¹: H; or lower        alkyl; or R³³ and R⁸¹ taken together form: —(CH₂)₂₋₆—;        —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where        R⁵⁷: H; or lower alkyl); —(CH₂)_(o)N(R²⁰)COR⁶⁴ (where: R²⁰: H;        or lower alkyl; R⁶⁴: lower alkyl; or lower alkenyl);        —(CH₂)_(o)COOR⁶⁷ (where R⁵⁷: lower alkyl; or lower alkenyl);        —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl; or lower alkenyl;        and R⁵⁹: H; or lower alkyl; or R⁵⁸ and R⁵⁹ taken together form:        —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or lower alkenyl);        —(CH₂)_(o)SO₂R⁶² (where R⁶²: lower alkyl; or lower alkenyl); or        —(CH₂)_(o)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower alkyl; lower        alkenyl; or lower alkoxy).    -   R¹⁷: lower alkyl; lower alkenyl; —(CH₂)_(q)OR⁵⁵ (where R⁵⁵:        lower alkyl; or lower alkenyl); —(CH₂)_(m)SR⁵⁶ (where R⁵⁶: lower        alkyl; or lower alkenyl); —(CH₂)_(q)NR³³R³⁴ (where R³³: lower        alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴        taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl); —(CH₂)_(q)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; or        lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together        form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(q)NR²⁰CONR³³R⁸¹ (where R²⁰: H; or lower lower alkyl;        R³³: H; or lower alkyl; or lower alkenyl; R⁸¹: H; or lower        alkyl; or R³³ and R⁸¹ taken together form: —(CH₂)₂₋₆—;        —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where        R⁵⁷: H; or lower alkyl); —(CH)_(q)N(R²⁰)COR⁶⁴ (where: R²⁰: H; or        lower alkyl; R⁶⁴: lower alkyl; or lower alkenyl);        —(CH₂)_(r)COOR⁵⁷ (where R⁵⁷: lower alkyl; or lower alkenyl);        —(CH₂)_(q)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl; or lower alkenyl;        and R⁵⁹: H; lower alkyl; or R⁵⁸ and R⁵⁹ taken together form:        —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(r)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or lower alkenyl);        —(CH₂)_(r)SO₂R⁶² (where R⁶²: lower alkyl; or lower alkenyl); or        —(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower alkyl; lower        alkenyl; or lower alkoxy).

Among the building blocks A1 to A69 and A105 the following arepreferred: A5 with R² being H, A8, A22, A25, A38 with R² being H, A42,A47, A50 and A105. Most preferred are building blocks of type A8′:

wherein R²⁰ is H or lower alkyl; and R⁶⁴ is alkyl; alkenyl; aryl;aryl-lower alkyl; or heteroaryl-lower alkyl; especially those whereinR⁶⁴ is n-hexyl (A8′-1); n-heptyl (A8′-2); 4-(phenyl)benzyl (A8′-3);diphenylmethyl (A8′-4); 3-amino-propyl (A8′-5); 5-amino-pentyl (A8′-6);methyl (A8′-7); ethyl (A8′-8); isopropyl (A8′-9); isobutyl (A8′-10);n-propyl (A8′-11); cyclohexyl (A8′-12); cyclohexylmethyl (A8′-13);n-butyl (A8′-14); phenyl (A8′-15); benzyl (A8′-16); (3-indolyl)methyl(A8′-17); 2-(3-indolyl)ethyl (A8′-18); (4-phenyl)phenyl (A8′-19); andn-nonyl (A8′-20).

Building block A70 belongs to the class of open-chain α-substitutedα-amino acids, building blocks A71 and A72 to the corresponding β-aminoacid analogues and building blocks A73-A104 to the cyclic analogues ofA70. Such amino acid derivatives have been shown to constrain smallpeptides in well defined reverse turn or U-shaped conformations (C. M.Venkatachalam, Biopolymers 1968, 6, 1425-1434; W. Kabsch, C. Sander,Biopolymers 1983, 22, 2577). Such building blocks or templates areideally suited for the stabilization of β-hairpin conformations inpeptide loops (D. Obrecht, M. Altorfer, J. A. Robinson, “Novel PeptideMimetic Building Blocks and Strategies for Efficient Lead Finding”, Adv.Med. Chem. 1999, Vol. 4, 1-68; P. Balaram, “Non-standard amino acids inpeptide design and protein engineering”, Curr. Opin. Struct. Biol. 1992,2, 845-851; M. Crisma, G. Valle, C. Toniolo, S. Prasad, R. B. Rao, P.Balaram, “β-turn conformations in crystal structures of model peptidescontaining α.α-disubstituted amino acids”, Biopolymers 1995, 35, 1-9; V.J. Hruby, F. Al-Obeidi, W. Kazmierski, Biochem. J. 1990, 268, 249-262).

It has been shown that both enantiomers of building blocks -A70-CO— toA104-CO— in combination with a building block -B-CO— being an α-aminoacid with L-configuration can efficiently stabilize and induce β-hairpinconformations (D. Obrecht, M. Altorfer, J. A. Robinson, “Novel PeptideMimetic Building Blocks and Strategies for Efficient Lead Finding”, Adv.Med. Chem. 1999, Vol. 4, 1-68; D. Obrecht, C. Spiegler, P. Schönholzer,K. Müller, H. Heimgartner, F. Stierli, Helv. Chim. Acta 1992, 75,1666-1696; D. Obrecht, U. Bohdal, J. Daly, C. Lehmann, P. Schönholzer,K. Müller, Tetrahedron 1995, 51, 10883-10900; D. Obrecht, C. Lehmann, C.Ruffieux, P. Schönholzer, K. Müller, Helv. Chim. Acta 1995, 78,1567-1587; D. Obrecht, U. Bohdal, C. Broger, D. Bur, C. Lehmann, R.Ruffieux, P. Schönholzer, C. Spiegler, Helv. Chim. Acta 1995, 78,563-580; D. Obrecht, H. Karajiannis, C. Lehmann, P. Schönholzer, C.Spiegler, Helv. Chim. Acta 1995, 78, 703-714).

Thus, for the purposes of the present invention templates (a1) and (a2)can also consist of -A70-CO— to A104-CO— or -A106-CO— to A110-CO— wherebuilding block A70 to A104 or A106 to A110 is of either (D)- or(L)-configuration, in combination with a building block -B-CO— of (L)-configuration.

Preferred values for R²⁰ in A70 to A104 are H or lower alkyl with methylbeing most preferred. Preferred values for R¹⁸, R¹⁹ and R²¹-R²⁹ inbuilding blocks A70 to A104 are the following:

-   -   R¹⁸: lower alkyl.    -   R¹⁹: lower alkyl; lower alkenyl; —(CH₂)_(p)OR⁵⁵ (where R⁵⁵:        lower alkyl; or lower alkenyl); —(CH₂)_(p)SR⁵⁶ (where R⁵⁶: lower        alkyl; or lower alkenyl); —(CH₂)_(p)NR³³R³⁴ (where R³³: lower        alkyl; or lower alkenyl; R³⁹: H; or lower alkyl; or R³³ and R³⁴        taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl); —(CH₂)_(p)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; or        lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together        form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(p)NR²⁶CONR³³R⁸¹ (where R²⁰: H; or lower lower alkyl;        R³³: H; or lower alkyl; or lower alkenyl; R⁸¹: H; or lower        alkyl; or R³³ and R⁸¹ taken together form: —(CH₂)₂₋₆—;        —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where        R⁵⁷: H; or lower alkyl); —(CH₂)_(p)N(R²⁰)COR⁶⁴ (where: R²⁰: H;        or lower alkyl; R⁶⁹: lower alkyl; or lower alkenyl);        —(CH₂)_(p)COOR⁵⁷ (where R⁵⁷: lower alkyl; or lower alkenyl);        —(CH₂)_(p)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl; or lower alkenyl;        and R⁵⁹: H; or lower alkyl; or R⁵⁸ and R⁵⁹ taken together form:        —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(o)PO(OR⁶⁹)₂ (where R⁶⁰: lower alkyl; or lower alkenyl);        —(CH₂)_(p)SO₂R⁶² (where R⁶²: lower alkyl; or lower alkenyl); or        —(CH₂)_(o)O₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower alkyl; lower        alkenyl; or lower alkoxy).    -   R²¹: H; lower alkyl; lower alkenyl; —(CH₂)_(o)OR⁵⁵ (where R⁵⁵:        lower alkyl; or lower alkenyl); —(CH₂)_(o)SR⁵⁶ (where R⁵⁶: lower        alkyl; or lower alkenyl); —(CH₂)_(o)NR³³R³⁴ (where R³³: lower        alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴        taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ : H; or lower        alkyl); —(CH₂)_(o)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; or        lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together        form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(o)NR²⁰CONR³³R⁸¹ (where R²⁰: H; or lower lower alkyl;        R³³: H; or lower alkyl; or lower alkenyl; R⁸¹: H; or lower        alkyl; or R³³ and R⁸¹ taken together form: —(CH₂)₂₋₆—;        —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where        R⁵⁷: H; or lower alkyl); —(CH₂)_(o)N(R²⁰)COR⁶⁴ (where: R²⁰: H;        or lower alkyl; R⁶⁴: lower alkyl; or lower alkenyl);        —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷: lower alkyl; or lower alkenyl);        —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl, or lower alkenyl;        and R⁵⁹: H; lower alkyl; or R⁵⁸ and R⁵⁹ taken together form:        —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)^(o)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or lower alkenyl);        —(CH₂)_(o)SO₂R⁶² (where R⁶²: lower alkyl; or lower alkenyl); or        —(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower alkyl; lower        alkenyl; or lower alkoxy).    -   R²²: lower alkyl; lower alkenyl; —(CH₂)_(o)OR⁵⁵ (where R⁵⁵:        lower alkyl; or lower alkenyl); —(CH₂)_(o)SR⁵⁶ (where R⁵⁶: lower        alkyl; or lower alkenyl); —(CH₂)_(o)NR³³R³⁴ (where R³³: lower        alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴        taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl); —(CH₂)_(o)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; or        lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together        form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂—;        where R⁵⁷: H; or lower alkyl); —(CH₂)_(o)NR²⁰CONR³³R⁸¹ (where        R²⁰: H; or lower lower alkyl; R³³: H; or lower alkyl; or lower        alkenyl; R⁸¹: H; or lower alkyl; or R³³ and R⁸¹ taken together        form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(o)N(R²⁰)COR⁶⁴ (where: R²⁰: H; or lower alkyl; R⁶⁴: lower        alkyl; or lower alkenyl); —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷: lower        alkyl; or lower alkenyl); —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower        alkyl, or lower alkenyl; and R⁵⁹: H; lower alkyl; or R⁵⁸ and R⁵⁹        taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl); —(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or lower        alkenyl); —(CH₂)_(o)SO₂R⁶² (where R⁶²: lower alkyl; or lower        alkenyl); or —(CH₂)_(o)C₆H₄R⁸ (where R⁸: H; F; Cl; CF; lower        alkyl; lower alkenyl; or lower alkoxy).    -   R²³: H; lower alkyl; lower alkenyl; —(CH₂)_(o)OR⁵⁵ (where R⁵⁵:        lower alkyl; or lower alkenyl); —(CH₂)_(o)SR⁵⁶ (where R⁵⁶: lower        alkyl; or lower alkenyl); —(CH₂)_(o)NR³³R³⁴ (where R³³: lower        alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴        taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl); —(CH₂)_(o)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; or        lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together        form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(o)NR²⁰CONR³³R⁸¹ (where R²⁰: H; or lower lower alkyl;        R³³: H; or lower alkyl; or lower alkenyl; R⁸¹ : H; or lower        alkyl; or R³³ and R⁸¹ taken together form: —(CH₂)₂₋₆—;        —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where        R⁵⁷: H; or lower alkyl); —(CH₂)_(o)N(R²⁰)COR⁶⁴ (where: R²⁰: H;        or lower alkyl; R⁶⁴: lower alkyl; or lower alkenyl);        particularly favoured are NR²⁰CO-lower alkyl (R²⁰: H; or lower        alkyl); —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷: lower alkyl; or lower        alkenyl); —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl, or lower        alkenyl; and R⁵⁹: H; lower alkyl; or R⁵⁸ and R⁵⁹ taken together        form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or lower alkenyl);        —(CH₂)_(o)SO₂R⁶² (where R⁶²: lower alkyl; or lower alkenyl); or        —(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower alkyl; lower        alkenyl; or lower alkoxy).    -   R²⁴: lower alkyl; lower alkenyl; —(CH₂)_(o)OR⁵⁵ (where R⁵⁵:        lower alkyl; or lower alkenyl); —(CH₂)_(o)SR⁵⁶ (where R⁵⁶: lower        alkyl; or lower alkenyl); —(CH₂)_(o)NR³³R³⁴ (where R³³: lower        alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴        taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl); —(CH₂)_(o)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; or        lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together        form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(o)NR²⁰CONR³³R⁸¹ (where R²⁰: H; or lower lower alkyl;        R³³: H; or lower alkyl; or lower alkenyl; R⁸¹: H; or lower        alkyl; or R³³ and R⁸¹ taken together form: —(CH₂)₂₋₆—;        —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where        R⁵⁷: H; or lower alkyl); —(CH₂)_(o)N(R²⁰)COR⁶⁴ (where: R²⁰: H;        or lower alkyl; R⁶⁴: lower alkyl; or lower alkenyl);        particularly favoured are NR²⁰CO-lower alkyl (R²⁰: H; or lower        alkyl); —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷: lower alkyl; or lower        alkenyl); —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl, or lower        alkenyl; and R⁵⁹: H; lower alkyl; or R⁵⁸ and R⁵⁹ taken together        form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or lower alkenyl);        —(CH₂)_(o)SO₂R⁶² (where R⁶²: lower alkyl; or lower alkenyl); or        —(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower alkyl; lower        alkenyl; or lower alkoxy).    -   R²⁵: H; lower alkyl; lower alkenyl; —(CH₂)_(m)OR⁵⁵ (where R⁵⁵:        lower alkyl; or lower alkenyl); —(CH₂)_(m)NR³³R³⁴ (where R³³:        lower alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³        and R³⁴ taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ : H; or lower        alkyl); —(CH₂)_(m)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; or        lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together        form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(m)NR²⁰CONR³³R⁸¹ (where R²⁰H; or lower lower alkyl; R³³:        H; or lower alkyl; or lower alkenyl; R⁸¹: H; or lower alkyl; or        R³³ and R⁸¹ taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl); —(CH₂)_(m)N(R²⁰)COR⁶⁴ (where: R²⁰: H; or lower alkyl;        R⁶⁴: lower alkyl; or lower alkenyl); —(CH₂)_(o)COOR⁵⁷ (where        R⁵⁷: lower alkyl; or lower alkenyl); —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where        R⁵⁸: lower alkyl; or lower alkenyl; and R⁵⁹: H; lower alkyl; or        R⁵⁸ and R⁵⁹ taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl); —(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or lower        alkenyl); —(CH₂)_(o)SO₂R⁶² (where R⁶²: lower alkyl; or lower        alkenyl); or —(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower        alkyl; lower alkenyl; or lower alkoxy).    -   R²⁶: H; lower alkyl; lower alkenyl; —(CH₂)_(m)OR⁵⁵ (where R⁵⁵:        lower alkyl; or lower alkenyl); —(CH₂)_(m)NR³³R³⁴ (where R³³:        lower alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³        and R³⁴ taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl); —(CH₂)_(m)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; or        lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together        form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(m)NR²⁰CONR³³K⁸¹ (where R²⁰: H; or lower lower alkyl;        R³³: H; or lower alkyl; or lower alkenyl; R⁸¹: H; or lower        alkyl; or R³³ and R⁸¹ taken together form: —(CH₂)₂₋₆—;        —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where        R⁵⁷: H; or lower alkyl); —(CH₂)_(m)N(R²⁰)COR⁶⁴ (where: R²⁰: H;        or lower alkyl; R⁶⁴: lower alkyl; or lower alkenyl);        —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷: lower alkyl; or lower alkenyl);        —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl; or lower alkenyl;        and R⁵⁹: H; lower alkyl; or R⁵⁸ and R⁵⁹ taken together form:        —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or lower alkenyl);        —(CH₂)_(o)SO₂R⁶² (where R⁶²: lower alkyl; or lower alkenyl); or        —(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower alkyl; lower        alkenyl; or lower alkoxy).    -   Alternatively, R²⁵ and R²⁶ taken together can be —(CH₂)₂₋₆—;        —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where        R⁵⁷: H; or lower alkyl).    -   R²⁷: H; lower alkyl; lower alkenyl; —(CH₂)_(o)OR⁵⁵ (where R⁵⁵:        lower alkyl; or lower alkenyl); —(CH₂)_(o)SR⁵⁶ (where R⁵⁶: lower        alkyl; or lower alkenyl); —(CH₂)_(o)NR³³R³⁴ (where R³³: lower        alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴        taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(OH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl); —(CH₂)_(o)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; or        lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together        form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(o)NR²⁰CONR³³R⁸¹ (where R²⁰: H; or lower lower alkyl;        R³³: H; or lower alkyl; or lower alkenyl; R⁸¹: H; or lower        alkyl; or R³³ and R⁸¹ taken together form: —(CH₂)₂₋₆—;        —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where        R⁵⁷: H; or lower alkyl); —(CH₂)_(o)N(R²⁰)COR⁶⁴ (where: R²⁰: H;        or lower alkyl; R⁶⁴: lower alkyl; or lower alkenyl);        —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷: lower alkyl; or lower alkenyl);        —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl, or lower alkenyl;        and R⁵⁹: H; lower alkyl; or R⁵⁸ and R⁵⁹ taken together form:        —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; lower alkyl);        —(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or lower alkenyl);        —(CH₂)_(o)SO₂R⁶² (where R⁶²: lower alkyl; or lower alkenyl); or        —(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower alkyl; lower        alkenyl; or lower alkoxy).    -   R²⁸: lower alkyl; lower alkenyl; —(CH₂)_(o)OR⁵⁵ (where R⁵⁵:        lower alkyl; or lower alkenyl); —(CH₂)_(o)SR⁵⁶ (where R⁵⁶: lower        alkyl; or lower alkenyl); —(CH₂)_(o)NR³³R³⁴ (where R³³: lower        alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴        taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl); —(CH₂)_(o)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; or        lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together        form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(o)NR²⁰CONR³³R⁸¹ (where R²⁰: H; or lower lower alkyl;        R³³: H; or lower alkyl; or lower alkenyl; R⁸¹: H; or lower        alkyl; or R³³ and R⁸¹ taken together form: —(CH₂)₂₋₆—;        —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where        R⁵⁷: H; or lower alkyl); —(CH₂)_(o)N(R²⁰)COR⁶⁴ (where: R²⁰: H;        or lower alkyl; R⁶⁴: lower alkyl; or lower alkenyl);        —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷: lower alkyl; or lower alkenyl);        —(CH₂)_(l)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl, or lower alkenyl;        and R⁵⁹: H; lower alkyl; or R⁵⁸ and R⁵⁹ taken together form:        —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or lower alkenyl);        —(CH₂)_(o)SO₂R⁶² (where R⁶²: lower alkyl; or lower alkenyl); or        —(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower alkyl; lower        alkenyl; or lower alkoxy).    -   R²⁹: lower alkyl; lower alkenyl; —(CH₂)_(o)OR⁵⁵ (where R⁵⁵:        lower alkyl; or lower alkenyl); —(CH₂)_(o)SR⁵⁶ (where R⁵⁶: lower        alkyl; or lower alkenyl); —(CH₂)_(o)NR³³R³⁴ (where R³³: lower        alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴        taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl); —(CH₂)_(o)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; or        lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together        form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(o)NR²⁰CONR³³R⁸¹ (where R²⁰: H; or lower lower alkyl;        R³³: H; or lower alkyl; or lower alkenyl; R⁸¹: H; or lower        alkyl; or R³³ and R⁸¹ taken together form: —(CH₂)₂₋₆—;        —(CH₂)₂O(CH₂)—; —(CH₂)₂S(CH₂)—; or —(CH₂)₂NR⁵⁷(CH₂)—; where R⁵⁷:        H; or lower alkyl); —(CH₂)_(o)N(R^(m))COR⁶⁴ (where: R²⁰: H; or        lower alkyl; R⁶⁴: lower alkyl; or lower alkenyl); particularly        favored are NR²⁰CO-lower-alkyl (R²⁰: H; or lower alkyl);        —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷: lower alkyl; or lower alkenyl);        —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl, or lower alkenyl;        and R⁵⁹: H; lower alkyl; or R⁵⁸ and R⁵⁹ taken together form:        —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(o)PO(OR^(H))₂ (where R⁶²: lower alkyl; or lower        alkenyl); —(CH₂)_(o)SO₂R⁶² (where R⁶²: lower alkyl; or lower        alkenyl); or —(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower        alkyl; lower alkenyl; or lower alkoxy).

For templates (b) to (p), such as (b1) and (c1), the preferred valuesfor the various symbols are the following:

-   -   R⁸: H; F; Cl; CF₃; lower alkyl; lower alkenyl; —(CH₂)_(o)OR⁵⁵        (where R⁵⁵: lower alkyl; or lower alkenyl); —(CH₂)_(o)SR⁵⁶        (where R⁵⁶: lower alkyl; or lower alkenyl); —(CH₂)_(o)NR³³R³⁴        (where R³³: lower alkyl; or lower alkenyl; R³⁴: H; or lower        alkyl; or R³³ and R³⁴ taken together form: —(CH₂)₂₋₆—;        —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where        R⁵⁷: H; or lower alkyl); —(CH₂)_(o)OCONR³³R⁷⁵ (where R³³: H; or        lower alkyl; or lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵        taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl); —(CH₂)_(o)NR²⁰CONR³³R⁸¹ (where R²⁰: H; or lower lower        alkyl; R³³: H; or lower alkyl; or lower alkenyl; R⁸¹: H; or        lower alkyl; or R³³ and R⁸¹ taken together form: —(CH₂)₂₋₆—;        —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷:        H; or lower alkyl); —(CH₂)_(o)N(R²⁰)COR⁶⁴ (where: R²⁰: H; or        lower alkyl; R⁶⁴: lower alkyl; or lower alkenyl);        —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷: lower alkyl; or lower alkenyl);        —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl; or lower alkenyl;        and R⁵⁹: H; or lower alkyl; or R⁵⁸ and R⁵⁹ taken together form:        —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or lower alkenyl);        —(CH₂)_(o)SO₂R⁶² (where R⁶²: lower alkyl; or lower alkenyl); or        —(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower alkyl; lower        alkenyl; or lower alkoxy).    -   R²⁰: H; or lower alkyl.    -   R³⁰: H; or methyl.    -   R³¹: H; lower alkyl; lower alkenyl; —(CH₂)_(p)OR⁵⁵ (where R⁵⁵:        lower alkyl; or lower alkenyl); —(CH₂)_(p)NR²³R²⁴ (where R³³:        lower alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³        and R³⁴ taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl); —(CH₂)_(p)OCONR³²R⁷⁵ (where R³³: H; or lower alkyl; or        lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together        form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(p)NR²⁰CONR²² R⁸¹ (where R²⁰: H; or lower lower alkyl;        R³³: H; or lower alkyl; or lower alkenyl; R⁸¹: H; or lower        alkyl; or R³³ and R⁸¹ taken together form: —(CH₂)₂₋₆—;        —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where        R⁵⁷: H; or lower alkyl); —(CH₂)_(p)N(R²⁰)COR⁶⁴ (where: R²⁰: H;        or lower alkyl; R⁶⁴: lower alkyl; or lower alkenyl);        —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷: lower alkyl; or lower alkenyl);        (—CH₂)_(o)CoNR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl, or lower alkenyl;        and R⁵⁹: H; lower alkyl; or R⁵⁸ and R⁵⁹ taken together form:        —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or lower alkenyl);        —(CH₂)_(o)SO₂R⁶² (where R⁶²: lower alkyl; or lower alkenyl); or        —(CH₂)_(r)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower alkyl; lower        alkenyl; or lower alkoxy); most preferred is —CH₂CONR⁵⁸R⁵⁹ (R⁵⁸:        H; or lower alkyl; R⁵⁹: lower alkyl; or lower alkenyl).    -   R³²: H; or methyl.    -   R³³: lower alkyl; lower alkenyl; —(CH₂)_(m)OR⁵⁵ (where R⁵⁵:        lower alkyl; or lower alkenyl); —(CH₂)_(m)NR³⁴R⁶³ (where R³⁴:        lower alkyl; or lower alkenyl; R⁶³: H; or lower alkyl; or R³⁴        and R⁶³ taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl); —(CH₂)_(m)OCONR⁷⁵R⁸² (where R⁷⁵: lower alkyl; or lower        alkenyl; R⁸²: H; or lower alkyl; or R⁷⁵ and R⁸² taken together        form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(m)NR²⁰CONR⁷⁸R⁸¹ (where R²⁰: H; or lower lower alkyl;        R⁷⁸: H; or lower alkyl; or lower alkenyl; R⁸¹: H; or lower        alkyl; or R⁷⁸ and R⁸¹ taken together form: —(CH₂)₂₋₆—;        —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where        R⁵⁷: H; or lower alkyl); —(CH₂)_(m)N(R²⁰)COR⁶⁴ (where: R²⁰: H;        or lower alkyl; R⁶⁴: lower alkyl; or lower alkenyl);        —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷: lower alkyl; or lower alkenyl);        —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl; or lower alkenyl;        and R⁵⁹: H; lower alkyl; or R⁵⁸ and R⁵⁹ taken together form:        —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl).    -   R³⁴: H; or lower alkyl.    -   R³⁵: H; lower alkyl; lower alkenyl; —(CH₂)_(m)OR⁵⁵ (where R⁵⁵:        lower alkyl; or lower alkenyl); —(CH₂)_(m)NR³³R³⁴ (where R³³:        lower alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³        and R³⁴ taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl); —(CH₂)_(m)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; or        lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together        form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(m)NR²⁰CONR³³R⁸¹(where R²⁰: H; or lower lower alkyl; R³³:        H; or lower alkyl; or lower alkenyl; R⁸¹: H; or lower alkyl; or        R³³ and R⁸¹ taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl); —(CH₂)_(m)N(R^(m))COR⁶⁴ (where: R²⁰: H; or lower alkyl;        R⁶⁴: lower alkyl; or lower alkenyl); —(CH₂)_(o)COOR⁵⁷ (where        R⁵⁷: lower alkyl; or lower alkenyl); —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where        R⁵⁸: lower alkyl; or lower alkenyl; and R⁵⁹: H; lower alkyl; or        R⁵⁸ and R⁵⁹ taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl).    -   R³⁶: lower alkyl; lower alkenyl; or aryl-lower alkyl.    -   R³⁷: H; lower alkyl; lower alkenyl; —(CH₂)_(p)OR⁵⁵ (where R⁵⁵:        lower alkyl; or lower alkenyl); —(CH₂)_(p)NR³³R³⁴ (where R³³:        lower alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³        and R³⁴ taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl); —(CH₂)_(p)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; or        lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together        form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(p)NR²⁰OONR³³R⁸¹ (where R²⁰: H; or lower alkyl; R³³: H;        or lower alkyl; or lower alkenyl; R⁸¹: H; or lower alkyl; or R³³        and R⁸¹ taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl); —(CH₂)_(p)N(R²⁰)COR⁶⁴ (where: R²⁰: H; or lower alkyl;        R⁶⁴: lower alkyl; or lower alkenyl); —(CH₂),COOR⁵⁷ (where R⁵⁷:        lower alkyl; or lower alkenyl); —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸:        lower alkyl, or lower alkenyl; and R⁵⁹: H; lower alkyl; or R⁵⁸        and R⁵⁹ taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl); —(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or lower        alkenyl); —(CH₂)_(o)SO₂R⁶² (where R⁶²: lower alky; or lower        alkenyl); or —(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower        alkyl; lower alkenyl; or lower alkoxy).    -   R³⁸: H; lower alkyl; lower alkenyl; —(CH₂)_(p)OR⁵⁵ (where R⁵⁵:        lower alkyl; or lower alkenyl); —(CH₂)_(p)NR³³R³⁴ (where R³³:        lower alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³        and R³⁴ taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl); —(CH₂)_(p)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; or        lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁸ taken together        form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(p)NR²⁰OCNR³³R⁸¹ (where R²⁰: H; or lower lower alkyl;        R³³: H; or lower alkyl; or lower alkenyl; R⁸¹: H; or lower        alkyl; or R³³ and R⁸¹ taken together form: —(CH₂)₂₋₆—;        —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where        R⁵⁷: H; or lower alkyl); —(CH₂)_(p)N(R²⁰)COR⁵⁴ (where: R²⁰: H;        or lower alkyl; R⁶⁴: lower alkyl; or lower alkenyl);        —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷: lower alkyl; or lower alkenyl);        —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl, or lower alkenyl;        and R⁵⁹: H; lower alkyl; or R⁵⁸ and R⁵⁹ taken together form:        —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or lower alkenyl);        —(CH₂)_(o)SO₂R⁸² (where R⁶²: lower alkyl; or lower alkenyl); or        —(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower alkyl; lower        alkenyl; or lower alkoxy).    -   R³⁹: H; lower alkyl; lower alkenyl; —(CH₂)_(m)OR⁵⁵ (where R⁵⁵:        lower alkyl; or lower alkenyl); —(CH₂)_(m)N(R²⁰)COR⁶⁴ (where:        R²⁰: H; or lower alkyl; R⁶⁴: lower alkyl; or lower alkenyl);        —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷: lower alkyl; or lower alkenyl);        —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl; or lower alkenyl;        and R⁵⁹: H; lower alkyl; or R⁵⁶ and R⁵⁹ taken together form:        —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl).    -   R⁴⁰: lower alkyl; lower alkenyl; or aryl-lower alkyl.    -   R⁴¹: H; lower alkyl; lower alkenyl; —(CH₂)_(p)OR⁵⁵ (where R⁵⁵:        lower alkyl; or lower alkenyl); —(CH₂)_(p)NR³³R³⁴ (where R³³:        lower alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³        and R³⁴ taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl); —(CH₂)_(p)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; or        lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together        form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(p)NR²⁰CONR³³R⁸¹ (where R²⁰: H; or lower lower alkyl;        R³³: H; or lower alkyl; or lower alkenyl; R⁸¹: H; or lower        alkyl; or R³³ and R⁸¹ taken together form: —(CH₂)₂₋₆—;        —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where        R⁵⁷: H; or lower alkyl); —(CH₂)_(p)N(R²⁰)COR⁶⁴ (where: R²⁰: H;        or lower alkyl; R⁶⁴: lower alkyl; or lower alkenyl);        —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷: lower alkyl; or lower alkenyl);        —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl, or lower alkenyl;        and R⁵⁹: H; lower alky; or R⁵⁸ and R⁵⁹ taken together form:        —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or lower alkenyl);        —(CH₂)_(o)SO₂R⁶² (where R⁶²: lower alkyl; or lower alkenyl); or        —(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower alkyl; lower        alkenyl; or lower alkoxy).    -   R⁴²: H; lower alkyl; lower alkenyl; —(CH₂)_(p)OR⁵⁵ (where R⁵⁵:        lower alkyl; or lower alkenyl); —(CH₂)_(p)NR³³R³⁴ (where R³³:        lower alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³        and R³⁴ taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl); —(CH₂)_(p)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; or        lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together        form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(p)NR²⁰CONR³³ R⁸¹ (where R²⁰: H; m or lower lower alkyl;        R³³: H; or lower alkyl; or lower alkenyl; R⁶¹: H; or lower        alkyl; or R³³ and R⁸¹ taken together form: —(CH₂)₂₋₆—;        —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where        R⁵⁷: H; or lower alkyl); —(CH₂)_(p)N(R²⁰)COR⁶⁴ (where: R²⁰: H;        or lower alkyl; R⁶⁴: lower alkyl; or lower alkenyl);        —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷: lower alkyl; or lower alkenyl);        —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl, or lower alkenyl;        and R⁵⁹: H; lower alkyl; or R⁵⁸ and R⁵⁹ taken together form:        —(CH₂)₂₋₆—: —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or lower alkenyl);        —(CH₂)_(o)SO₂R⁶² (where R⁶²: lower alkyl; or lower alkenyl); or        —(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower alkyl; lower        alkenyl; or lower alkoxy).    -   R⁴³: H; lower alkyl; lower alkenyl; —(CH₂)_(m)OR⁵⁵ (where R⁵⁵:        lower alkyl; or lower alkenyl); —(CH₂)_(m)SR⁵⁶ (where R⁵⁶: lower        alkyl; or lower alkenyl); —(CH₂)_(m)NR³³R³⁴ (where R³³: lower        alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴        taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl); —(CH₂)_(m)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; or        lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together        form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(m)NR²⁰CONR³³R⁸¹ (where R²⁰: H; or lower lower alkyl;        R³³: H; or lower alkyl; or lower alkenyl; R⁸¹: H; or lower        alkyl; or R³³ and R⁸¹ taken together form: —(CH₂)₂₋₆—;        —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where        R⁵⁷: H; or lower alkyl); —(CH₂)_(m)N(R²⁰)COR⁶⁴ (where: R²⁰: H;        or lower alkyl; R⁶⁴: lower alkyl; or lower alkenyl);        —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷: lower alkyl; or lower alkenyl);        —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl; or lower alkenyl;        and R⁵⁹: H; lower alkyl; or R⁵⁸ and R⁵⁹ taken together form:        —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or lower alkenyl);        —(CH₂)_(o)SO₂R⁶² (where R⁶²: lower alkyl; or lower alkenyl); or        —(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower alkyl; lower        alkenyl; or lower alkoxy).    -   R⁴⁴: lower alkyl; lower alkenyl; —(CH₂)_(p)OR⁵⁵ (where R⁵⁵:        lower alkyl; or lower alkenyl); —(CH₂)_(p)SR⁵⁶ (where R⁵⁶: lower        alkyl; or lower alkenyl); —(CH₂)_(p)NR³³R³⁴ (where R³³: lower        alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴        taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        (CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl); —(CH₂)_(p)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; or        lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁸ taken together        form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(p)NR²⁹CONR³³R⁸¹ (where R²⁰: H; or lower lower alkyl;        R³³: H; or lower alkyl; or lower alkenyl; R⁸¹: H; or lower        alkyl; or R³³ and R⁸¹ taken together form: —(CH₂)₂₋₆—;        —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where        R⁵⁷: H; or lower alkyl); —(CH₂)_(p)N(R²⁰)COR⁶⁴ (where: R²⁰: H;        or lower alkyl; R⁶⁴: lower alkyl; or lower alkenyl);        —(CH₂)_(p)COOR⁵⁷ (where R⁵⁷: lower alkyl; or lower alkenyl);        —(CH₂)_(p)CONR⁵⁸R⁵⁹ (where R⁵⁸ : lower alkyl; or lower alkenyl;        and R⁵⁹: H; lower alkyl; or R⁵⁸ and R⁵⁹ taken together form:        —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); or        —(CH₂)_(o)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower alkyl; lower        alkenyl; or lower alkoxy).    -   R⁴⁵: H; lower alkyl; lower alkenyl; —(CH₂)_(o)OR⁵⁵ (where R⁵⁵:        lower alkyl; or lower alkenyl); —(CH₂)_(o)SR⁵⁶ (where R⁵⁶: lower        alkyl; or lower alkenyl); —(CH₂)_(o)NR³³R³⁴ (where R³³: lower        alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴        taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl); —(CH₂)_(s)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; or        lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together        form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(o)NR²⁰CONR³³R⁸¹ (where R²⁰: H; or lower lower alkyl;        R³³: H; or lower alkyl; or lower alkenyl; R⁸¹: H; or lower        alkyl; or R³³ and R⁸¹ taken together form: —(CH₂)₂₋₆—;        —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where        R⁵⁷: H; or lower alkyl); —(CH₂)_(o)N(R²⁰)COR⁶⁴ (where: R²⁰): H;        or lower alkyl; R⁴¹: lower alkyl; or lower alkenyl);        —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷: lower alkyl; or lower alkenyl);        —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl; or lower alkenyl;        and R⁵⁹: H; lower alkyl; or R⁵⁸ and R⁵⁹ taken together form:        —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); or        —(CH₂)_(s)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower alkyl; lower        alkenyl; or lower alkoxy).    -   R⁴⁶: H; lower alkyl; lower alkenyl; —(CH₂)_(s)OR⁵⁵ (where R⁵⁵:        lower alkyl; or lower alkenyl); —(CH₂)_(s)SR⁵⁶ (where R⁵⁶: lower        alkyl; or lower alkenyl); —(CH₂)_(s)NR³³R³⁴ (where R³³: lower        alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴        taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl); —(CH₂)_(s)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; or        lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together        form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(s)NR²⁰CONR³³R⁸¹ (where R²⁰: H; or lower lower alkyl;        R³³: H; or lower alkyl; or lower alkenyl; R⁸¹: H; or lower        alkyl; or R³³ and R⁸¹ taken together form: —(CH₂)₂₋₆—;        —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where        R⁵⁷: H; or lower alkyl); —(CH₂)_(s)N(R²⁰)COR⁶⁴ (where: R²⁰: H;        or lower alkyl; R⁶⁴: lower alkyl; or lower alkenyl);        —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷: lower alkyl; or lower alkenyl);        —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl; or lower alkenyl;        and R⁵⁹: H; lower alkyl; or R⁵⁸ and R⁵⁹ taken together form:        —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); or        —(CH₂)_(s)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower alkyl; lower        alkenyl; or lower alkoxy).    -   R⁴⁷: H; or OR⁵⁵ (where R⁵⁵: lower alkyl; or lower alkenyl).    -   R⁴⁸: H; or lower alkyl.    -   R⁴⁹: H; lower alkyl; —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷: lower alkyl;        or lower alkenyl); —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl;        or lower alkenyl; and R⁵⁹: H; lower alkyl; or R⁵⁸ and R⁵⁹ taken        together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); or        —(CH₂)_(s)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower alkyl; lower        alkenyl; or lower alkoxy).    -   R⁵⁰: H; or methyl.    -   R⁵¹: H; lower alkyl; lower alkenyl; —(CH₂)_(m)OR⁵⁵ (where R⁵⁵:        lower alkyl; or lower alkenyl); —(CH₂)_(m)NR³³R³⁴ (where R³³:        lower alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³        and R³⁴ taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl); —(CH₂)_(m)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; or        lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together        form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(m)NR²⁰CONR³³R⁸¹ (where R²⁰: H; or lower alkyl; R³³: H;        or lower alkyl; or lower alkenyl; R⁸¹: H; or lower alkyl; or R³³        and R⁸¹ taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(OH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl); —(CH₂)_(m)N(R²⁰)COR⁶⁴ (where: R²⁰: H; or lower alkyl;        R⁶⁴: lower alkyl; or lower alkenyl); —(CH₂)_(p)COOR⁵⁷ (where        R⁵⁷: lower alkyl; or lower alkenyl); —(CH₂)_(p)CONR⁵⁸R⁵⁹ (where        R⁵⁸: lower alkyl; or lower alkenyl; and R⁵⁹: H; lower alkyl; or        R⁵⁸ and R⁵⁹ taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl); or —(CH₂)_(r)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower        alkyl; lower alkenyl; or lower alkoxy).    -   R⁵²: H; lower alkyl; lower alkenyl; —(CH₂)_(m)OR⁵⁵ (where R⁵⁵:

lower alkyl; or lower alkenyl); —(CH₂)_(m)NR³³R³⁴ (where R³³: loweralkyl; or lower alkenyl; R³⁹: H; or lower alkyl; or R³³ and R³⁴ takentogether form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); —(CH₂)_(m)OCONR³³R⁷⁵(where R³³: H; or lower alkyl; or lower alkenyl; R⁷⁵: lower alkyl; orR³³ and R⁷⁵ taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;—(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);—(CH₂)_(m)NR²⁶CONR³³R⁸¹ (where R²⁰: H; or lower lower alkyl; R³³: H; orlower alkyl; or lower alkenyl; R⁸¹: H; or lower alkyl; or R³³ and R⁸¹taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; R⁵⁷: H; or lower alkyl); —(CH₂)_(m)N(R²⁰)COR⁶⁴(where: R²⁰: H; or lower alkyl; R⁶⁴: lower alkyl; or lower alkenyl);—(CH₂)_(p)COOR⁵⁷ (where R⁵⁷: lower alkyl; or lower alkenyl);—(CH₂)_(p)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl; or lower alkenyl; and R⁵⁹:H; lower alkyl; or R⁵⁸ and R⁵⁹ taken together form: —(CH₂)₂₋₆—;—(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H;or lower alkyl); or —(CH₂)_(r)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; loweralkyl; lower alkenyl; or lower alkoxy).

-   -   R⁵³: H; lower alkyl; lower alkenyl; —(CH₂)_(m)OR⁵⁵ (where R⁵⁵:        lower alkyl; or lower alkenyl); —(CH₂)_(m)NR³³R³⁴ (where R³³:        lower alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³        and R³⁴ taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl); —(CH₂)_(m)OCONR³³R^(m) (where R³³: H; or lower alkyl; or        lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together        form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH,)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(m)NO²⁰CONR³³R⁸¹ (where R²⁰: H; or lower lower alkyl;        R³³: H; or lower alkyl; or lower alkenyl; R⁸¹: H; or lower        alkyl; or R³³ and R⁸¹ taken together form: —(CH₂)₂₋₆—;        —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where        R⁵⁷: H; or lower alkyl); —(CH₂)_(m)N(R²⁰)COR⁶⁴ (where: R²⁰: H;        or lower alkyl; R⁶⁴: lower alkyl; or lower alkenyl);        —(CH₂)_(p)COOR⁵⁷ (where R⁵⁷: lower alkyl; or lower alkenyl);        —(CH₂)_(p)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl; or lower alkenyl;        and R⁵⁹: H; lower alkyl; or R⁵⁸ and R⁵⁹ taken together form:        —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); or        —(CH₂)_(r)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower alkyl; lower        alkenyl; or lower alkoxy).    -   R⁵⁴: lower alkyl; lower alkenyl; or aryl-lower alkyl.

Among the building blocks A70 to A104 the following are preferred: A74with R²² being H, A75, A76, A77 with R²² being H, A78 and A79.

The building block -B-CO— within templates (a1) and (a2) designates anL-amino or an L-hydroxy acid residue. Preferred values for B are:—NR²⁰CH(R⁷¹)—, enantiomers of groups A5 with R² being H, A8, A22, A25,A38 with R² being H, A42, A47, and A50, and —OCH(R⁷¹)—, —OCH(R⁷²)—,—OCH(R⁷³)—, —OCH(R⁷⁴)— and —OCH(R⁸⁴)—. Most preferred building blocks-B-CO— are

Ala L-Alanine Arg L-Arginine Asn L-Asparagine Asp L-Aspartic acid CysL-Cysteine Gln L-Glutamine Glu L-Glutamic acid Gly Glycine HisL-Histidine Ile L-Isoleucine Leu L-Leucine Lys L-Lysine Met L-MethioninePhe L-Phenylalanine Pro L-Proline Ser L-Serine Thr L-Threonine TrpL-Tryptophan Tyr L-Tyrosine Val L-Valine Cit L-Citrulline OrnL-Ornithine tBuA L-t-Butylalanine Sar Sarcosine t-BuGL-tert.-Butylglycine 4AmPhe L-para-Aminophenylalanine 3AmPheL-meta-Aminophenylalanine 2AmPhe L-ortho-AminophenylalaninePhe(mC(NH₂)═NH) L-meta-Amidinophenylalanine Phe(pC(NH₂)═NH)L-para-Amidinophenylalanine Phe(mNHC(NH₂)═NH)L-meta-Guanidinophenylalanine Phe(pNHC(NH₂)═NH)L-para-Guanidinophenylalanine Phg L-Phenylglycine ChaL-Cyclohexylalanine C₄al L-3-Cyclobutylalanine C₅alL-3-Cyclopentylalanine Nle L-Norleucine 2-Nal L-2-Naphthylalanine 1-NalL-1-Naphthylalanine 4Cl-Phe L-4-Chlorophenylalanine 3Cl-PheL-3-Chlorophenylalanine 2Cl-Phe L-2-Chlorophenylalanine 3,4Cl₂-PheL-3,4-Dichlorophenylalanine 4F-Phe L-4-Fluorophenylalanine 3F-PheL-3-Fluorophenylalanine 2F-Phe L-2-Fluorophenylalanine TicL-1,2,3,4-Tetrahydroisoquinoline- 3-carboxylic acid ThiL-β-2-Thienylalanine Tza L-2-Thiazolylalanine Mso L-Methionine sulfoxideAcLys L-N-Acetyllysine Dpr L-2,3-Diaminopropionic acid A₂BuL-2,4-Diaminobutyric acid Dab (2S,3S)-2,3-Diaminobutyric acid Abuγ-Aminobutyric acid (GABA) Aha ε-Aminohexanoic acid Aibα-Aminoisobutyric acid Y(Bzl) L-O-Benzyltyrosine Bip L-BiphenylalanineS(Bzl) L-O-Benzylserine T(Bzl) L-O-Benzylthreonine hChaL-Homo-cyclohexylalanine hCys L-Homo-cysteine hSer L-Homo-serine hArgL-Homo-arginine hPhe L-Homo-phenylalanine Bpa L-4-BenzoylphenylalaninePip L-Pipecolic acid OctG L-Octylglycine MePhe L-N-MethylphenylalanineMeNle L-N-Methylnorleucine MeAla L-N-Methylalanine MeIleL-N-Methylisoleucine MeVal L-N-Methvaline MeLeu L-N-Methylleucine 4Hyp1(4S)-L-Hydroxyproline 4Hyp2 (4R)-L-Hydroxyproline 4Mp1(4S)-L-Mercaptoproline 4Mp2 (4R)-L-Mercaptoproline Oic(3aS,7aS)-L-1-Octahydro-1H-indole-2- carboxylic acid Glycolic acid Lac(2S)-2-Hydroxy-propanoic acid Hmb (2S)-2-Hydroxy-3-methylbutyric acidH3mp (2S,3S)-2-Hydroxy-3-methyl-pentanoic acid H4mp(2S)-2-Hydroxy-4-methyl-pentanoic acid Hmtb (2S)-2-Hydroxy-4-methylthiobutyric acid Hhpp (2S)-2-Hydroxy-3-(4′-hydroxyphenyl)- propionic acidHimp (2S)-2-Hydroxy-3-(Imidazole-4′-yl)- propionic-acid Hpp(2S)-2-Hydroxy-3-phenyl propionic acid Hinp(2S)-2-Hydroxy-3-(indol-3′-yl)-propionic acid Dhp(2S)-2,3-Dihydroxy-propionic acid Hbd (2S)-2-Hydroxybutanedioic acid Hpd(2S)-2-Hydroxy-pentanedioic acid Ahh (2S)-6-Amino-2-hydroxy-hexanoicacid Hgp (2S)-2-Hydroxy-5-guanidino-pentanoic acid Hmcp(2S)-2-Hydroxy-3-mercapto-propionic acid Haa 2-Hydroxy acetic acid Hcp2-Hydroxy-3-carbamoyl-propanoic acid Hcb 2-Hydroxy-4-carbamoyl-butanoicacid 3Dhb (2S,3R)-2,3-Dihydroxy-butyric acid Hpa(2S)-2-Hydroxy-2-phenylacetic acid Ahp (2S)-3-Amino-2-hydroxy-propionicacid Ahb (2S)-4-Amino-2-hydroxy butyric acid 3Ahb(2S,3S)-3-Amino-2-hydroxy butyric acid 4Dhb (2S)-2,4-Dihydroxy butyricacid Hmcb (2S)-2-Hydroxy-4-mercapto-butyric acid Hpb(2S)-2-Hydroxy-4-phenyl-butyric acid Hcb(2S)-2-Hydroxy-4-cyclohexyl-butyric acid Hgh(2S)-2-Hydroxy-6-guanidino-hexanoic acid Hcap2-Hydroxy-5-(carbamoylamino)pentanoic acid Ahp(2S)-5-Amino-2-hydroxy-pentanoic acid Hdmp (2S)-2-Hydroxy-4,4-dimethylpentanoic acid Hdmb (2S)-2-Hydroxy-3,3-dimethyl butyric acid Hchp(2S)-2-Hydroxy-3-cyclohexyl propionic acid Hcbp(2S)-2-Hydroxy-3-cyclobutyl propionic acid Hcpp(2S)-2-Hydroxy-3-cyclopentyl propionic acid Hca (2S)-2-Hydroxy caproicacid Hda (2S)-2-Hydroxy decanoic acid H2np(2S)-2-Hydroxy-3-(2′-naphthyl)propionic acid H1np(2S)-2-Hydroxy-3-(1′-naphthyl)propionic acid Hbp(23)-2-Hydroxy-3-biphenyl-4′-yl propionic acid 4Clphp(2S)-3-(4′-Chlorophenyl)-2-hydroxy propionic acid 3Clphp(2S)-3-(3′-Chlorophenyl)-2-hydroxy propionic acid 2Clphp(2S)-3-(2′-Chlorophenyl)-2-hydroxy propionic acid 4Fphp(2S)-3-(4′-Fluorophenyl)-2-hydroxypropionic acid 3Fphp(2S)-3-(3′-Fluorophenyl)-2-hydroxy propionic acid 2Fphp(2S)-3-(2′-Fluorophenyl)-2-hydroxy propionic acid Aahh(2S)-6-Acetylamino-2-hydroxy-hexanoic acid Hbpp(2S)-2-Hydroxy-3-4′-benzoylphenyl propionic acid Bhp(2S)-3-Benzyloxy-2-hydroxy-propionic acid Bhb(2S,3R)-3-Benzyloxy-2-hydroxy-butyric acid Hbpp(2S)-2-Hydroxy-3-(4′-benzyloxyphenyl)- propionic acid 4Hb 4-Hydroxybutyric acid 6Hh 6-Hydroxy hexanoic acid Hib 2-Hydroxy isobutyric acid

In addition, the most preferred values for B also include groups of typeA8″ of (L)-configuration:

wherein R²⁰ is H or lower alkyl and R⁶⁴ is alkyl; alkenyl;—[(CH₂)_(u)—X]_(t)—CH₃ (where X is —O—; —NR²⁰—, or —S—; u=1-3, andt=1-6), aryl; aryl-lower alkyl; or heteroaryl-lower alkyl; especiallythose wherein R⁶⁴ is n-hexyl (A8″-21); n-heptyl (A8″-22);4-(phenyl)benzyl (A8″-23); diphenylmethyl (A8″-24); 3-amino-propyl(A8″-25); 5-amino-pentyl (A8″-26); methyl (A8″-27); ethyl (A8″-28);isopropyl (A8″-29); isobutyl(A8″-30); n-propyl (A8″-31); cyclohexyl(A8″-32); cyclohexyl-methyl (A8″-33); n-butyl (A8″-34); phenyl (A8″-35);benzyl (A8″-36); (3-indolyl)methyl (A8″-37); 2-(3-indolyl)ethyl(A8″-38); (4-phenyl)-phenyl (A8″-39); n-nonyl (A8″-40);CH₃—OCH₂CH₂—OCH₂— (A8″-41) and CH₃—(OCH₂CH₂)₂—OCH₂— (A8′ -42).

In a particular embodiment the template is ^(D)Pro-^(L)Pro or^(L)Pro-^(D)Pro or a group corresponding thereto but in which the^(D)Pro moiety and/or the ^(L)Pro moiety is substituted as shown inFormula A8′ and, respectively, A8″, above.

The peptidic or depsipeptidic chain Z of the β-hairpin mimeticsdescribed herein is generally defined in terms of amino acid or hydroxyacid residues belonging to one of the following groups:

-   -   Group C —NR²⁰H(R⁷²)CO—; “hydrophobic: small to medium-sized”    -   Group D —NR²⁰CH(R⁷³)CO—; “hydrophobic: large aromatic or        heteroaromatic”    -   Group E —NR²⁰H(R⁷⁴)CO—; “polar-cationic” and “urea-derived”    -   Group F —NR²⁰CH(R⁸⁴)CO—; “polar-non-charged or anionic”    -   Group H —NR²⁰—CH(CO—)—(CH₂)₄₋₇—CH(CO—)—NR²⁰—;        —NR²⁰—CH(CO—)—(CH₂)_(p)SS(CH₂)_(p)—CH(CO—)—NR²⁰—;        —NR²⁰—CH(CO—)—(—(CH₂)_(p)NR²⁰CO(CH₂)_(p)—CH(CO—)—NR²⁰—; and        —NR²⁰—CH(CO—)—(—(CH₂)_(p)NR²⁰CONR²⁰(CH₂)_(p)—CH(CO—)—NR²⁰—;        -   “interstrand linkage”    -   Group L —OCH(R⁷¹)CO—; —OCH(R⁷²)CO—; —OCH(R⁷²)CO—; —OCH(R⁷⁴)CO—;        —OCH(R⁸⁴)CO—

Furthermore, the amino acid residues in chain Z can also be of formula-A-CO— wherein A is as defined above. Finally, Pro and Gly can also beamino acid residues and the residue of glycolic acid can also be ahydroxy acid residue in chain Z with the exception of positions whereinterstrand linkages (H) are possible.

Group C comprises amino acid residues with small to medium-sizedhydrophobic side chain groups according to the general definition forsubstituent R⁷². A hydrophobic residue refers to an amino acid sidechain that is uncharged at physiological pH and that is repelled byaqueous solution. Furthermore these side chains generally do not containhydrogen bond donor groups, such as (but not limited to) primary andsecondary amides, primary and secondary amines and the correspondingprotonated salts thereof, thiols, alcohols, phosphonates, phosphates,ureas or thioureas. However, they may contain hydrogen bond acceptorgroups such as ethers, thioethers, esters, tertiary amides, alkyl- oraryl phosphonates and phosphates or tertiary amines. Genetically encodedsmall-to-medium-sized hydrophobic amino acids include alanine,isoleucine, leucine, methionine and valine.

Group D comprises amino acid residues with aromatic and heteroaromaticside chain groups according to the general definition for substituentR⁷³. An aromatic amino acid residue refers to a hydrophobic amino acidhaving a side chain containing at least one ring having a conjugatedit-electron system (aromatic group). In addition they may containhydrogen bond donor groups such as (but not limited to) primary andsecondary amides, primary and secondary amines and the correspondingprotonated salts thereof, thiols, alcohols, phosphonates, phosphates,ureas or thioureas, and hydrogen bond acceptor groups such as (but notlimited to) ethers, thioethers, esters, tetriary amides, alkyl- or arylphosphonates -and phosphates or tertiary amines. Genetically encodedaromatic amino acids include phenylalanine and tyrosine.

A heteroaromatic amino acid residue refers to a hydrophobic amino acidhaving a side chain containing at least one ring having a conjugatedn-system incorporating at least one heteroatom such as (but not limitedto) O, S and N according to the general definition for substituent R⁷⁷.In addition such residues may contain hydrogen bond donor groups such as(but not limited to) primary and secondary amides, primary and secondaryamines and the corresponding protonated salts thereof, thiols, alcohols,phosphonates, phosphates, ureas or thioureas, and hydrogen bond acceptorgroups such as (but not limited to) ethers, thioethers, esters, tetriaryamides, alkyl- or aryl phosphonates -and phosphates or tertiary amines.Genetically encoded heteroaromatic amino acids include tryptophan andhistidine.

Group E comprises amino acids containing side chains withpolar-cationic, acylamino- and urea-derived residues according to thegeneral definition for substituent R⁷⁴. Polar-cationic refers to a basicside chain which is protonated at physiological pH. Genetically encodedpolar-cationic amino acids include arginine, lysine and histidine.Citrulline is an example for an urea derived amino acid residue.

Group F comprises amino acids containing side chains withpolar-non-charged or anionic residues according to the generaldefinition for substituent R⁸⁴. A polar-non-charged or anionic residuerefers to a hydrophilic side chain that is uncharged and, respectivelyanionic at physiological pH (carboxylic acids being included), but thatis not repelled by aqueous solutions. Such side chains typically containhydrogen bond donor groups such as (but not limited to) primary andsecondary amides, carboxyclic acids and esters, primary and secondaryamines, thiols, alcohols, phosphonates, phosphates, ureas or thioureas.These groups can form hydrogen bond networks with water molecules. Inaddition they may also contain hydrogen bond acceptor groups such as(but not limited to) ethers, thioethers, esters, tetriary amides,carboxylic acids and carboxylates, alkyl- or aryl phosphonates -andphosphates or tertiary amines. Genetically encoded polar-non-chargedamino acids include asparagine, cysteine, glutamine, serine andthreonine, but also aspartic acid and glutamic acid.

Group H comprises side chains of preferably (L)-amino acids at oppositepositions of the β-strand region that can form an interstrand linkage.The most widely known linkage is the disulfide bridge formed bycysteines and homo-cysteines positioned at opposite positions of theβ-strand. Various methods are known to form disulfide linkages includingthose described by: J. P. Tam et al. Synthesis 1979, 955-957; Stewart etal., Solid Phase Peptide Synthesis, 2d Ed., Pierce Chemical Company,III., 1984; Ahmed et al. J. Biol. Chem. 1975, 250, 8477-8482; andPennington et al., Peptides, pages 164-166, Giralt and Andreu, Eds.,ESCOM Leiden, The Netherlands, 1990. Most advantageously, for the scopeof the present invention, disulfide linkages can be prepared usingacetamidomethyl (Acm)-protective groups for cysteine. A well establishedinterstrand linkage consists in linking ornithines and lysines,respectively, with glutamic and aspartic acid residues located atopposite β-strand positions by means of an amide bond formation.Preferred protective groups for the side-chain amino groups of ornithineand lysine are allyloxycarbonyl (Alloc) and allylesters for aspartic andglutamic acid. Finally, interstrand linkages can also be established bylinking the amino groups of lysine and ornithine located at oppositeβ-strand positions with reagents such as N,N-carbonyl-imidazole to formcyclic ureas.

Group L comprises hydroxy acid residues with side chain groups accordingto the general definition for substituent R⁷¹; hydroxy acid residueswith small to medium-sized hydrophobic side chain groups according tothe general definition for substituent R⁷²; hydroxy acid residues witharomatic and heteroaromatic side chain groups according to the generaldefinition for substituent R⁷³; hydroxy acid residues withpolar-cationic, acylamino- and urea-derived side chain groups accordingto the general definition for substituent R⁷⁴; and hydroxy acid residueswith polar-non-charged or anionic groups according to the generaldefinition for substituent R⁸⁴. Hydrophobic side chain groups areuncharged at physiological pH and repelled by aqueous solution. Anaromatic side chain group is hydrophobic and contains at least one ringhaving a conjugated π-electron system (aromatic group). A heteroaromaticside chain group is hydrophobic and contains at least one ring having aconjugated n-system incorporating at least one heteroatom such as (butnot limited to) O, S and N according to the general definition forsubstituent R⁷⁷. A polar-cationic side chain group refers to a basicside chain which is protonated at physiological pH. A polar-non-chargedor anionic side chain group is uncharged and, respectively anionic atphysiological pH (carboxylic acids being included), but is not repelledby aqueous solutions.

As mentioned earlier, positions for interstrand linkages are positionsP4 and P11 taken together. Such interstrand linkages are known tostabilize the β-hairpin conformations and thus constitute an importantstructural element for the design of β-hairpin mimetics.

Most preferred amino acid residues in chain Z are those derived fromnatural α-amino acids. Hereinafter follows a list of amino and hydroxyacids which, or the residues of which, are suitable for the purposes ofthe present invention, the abbreviations corresponding to generallyadopted usual practice:

three letter code one letter code Ala L-Alanine A Arg L-Arginine R AsnL-Asparagine N Asp L-Aspartic acid D Cys L-Cysteine C Glu L-Glutamicacid E Gln L-Glutamine Q ^(D)Gln D-Glutamine ^(D)Q Gly Glycine G HisL-Histidine H Ile L-Isoleucine I Leu L-Leucine L Lys L-Lysine K MetL-Methionine M Phe L-Phenylalanine F Pro L-Proline P ^(D)Pro D-Proline^(D)P Ser L-Serine S ^(D)Ser D-Serine ^(D)S Thr L-Threonine T TrpL-Tryptophan W Tyr L-Tyrosine Y Val L-Valine V

Glycolic acid Lac (2S)-2-Hydroxy-propanoic acid Hmb(2S)-2-Hydroxy-3-methylbutyric acid H3mp(2S,3S)-2-Hydroxy-3-methyl-pentanoic acid H4mp(2S)-2-Hydroxy-4-methyl-pentanoic acid Hmtb (2S)-2-Hydroxy-4-methylthiobutyric acid Hhpp (2S)-2-Hydroxy-3-(4′-hydroxyphenyl)- propionic acidHimp (2S)-2-Hydroxy-3-(Imidazole-4′-yl)-propionic acid Hpp(2S)-2-Hydroxy-3-phenyl propionic acid Hinp(2S)-2-Hydroxy-3-(indol-3′-yl)-propionic acid Dhp(2S)-2,3-Dihydroxy-propionic acid Hbd (2S)-2-Hydroxybutanedioic acid Hpd(2S)-2-Hydroxy-pentanedioic acid Ahh (2S)-6-Amino-2-hydroxy-hexanoicacid Hgp (2S)-2-Hydroxy-5-guanidino-pentanoic acid Hmcp(2S)-2-Hydroxy-3-mercapto-propionic acid Haa 2-Hydroxy acetic acid Hcp2-Hydroxy-3-carbamoyl-propanoic acid Hcb 2-Hydroxy-4-carbamoyl-butanoicacid 3Dhb (2S,3R)-2,3-Dihydroxy-butyric acid

Other α-amino or hydroxy acids which, or the residues of which, aresuitable for the purposes of the present invention include:

Cit L-Citrulline Orn L-Ornithine tBuA L-t-Butylalanine Sar Sarcosine PenL-Penicillamine t-BuG L-tert.-Butylglycine 4AmPheL-para-Aminophenylalanine 3AmPhe L-meta-Aminophenylalanine 2AmPheL-ortho-Aminophenylalanine Phe(mC(NH₂)═NH) L-meta-AmidinophenylalaninePhe(pC(NH₂)═NH) L-para-Amidinophenylalanine Phe(mNHC(NH₂)═NH)L-meta-Guanidinophenylalanine Phe(pNHC(NH₂)═NH)L-para-Guanidinophenylalanine Phg L-Phenylglycine ChaL-Cyclohexylalanine C₄al L-3-Cyclobutylalanine C₅alL-3-Cyclopentylalanine Nle L-Norleucine 2-Nal L-2-Naphthylalanine 1-NalL-1-Naphthylalanine 4Cl-Phe L-4-Chlorophenylalanine 3Cl-PheL-3-Chlorophenylalanine 2Cl-Phe L-2-Chlorophenylalanine 3,4Cl₂-PheL-3,4-Dichlorophenylalanine 4F-Phe L-4-Fluorophenylalanine 3F-PheL-3-Fluorophenylalanine 2F-Phe L-2-Fluorophenylalanine Tic1,2,3,4-Tetrahydroisoquinoline-3-carboxylic acid Oic(2S,3aS,7aS)-1-Octahydro-1H-indole-2- carboxylic acid ThiL-β-2-Thienylalanine Tza L-2-Thiazolylalanine Mso L-Methionine sulfoxideAcLys N-Acetyllysine Dpr 2,3-Diaminopropionic acid A₂Bu2,4-Diaminobutyric acid Dab (S)-2,3-Diaminobutyric acid Abuγ-Aminobutyric acid (GABA) Aha ε-Aminohexanoic acid Aibα-Aminoisobutyric acid Y(Bzl) L-O-Benzyltyrosine BipL-(4-phenyl)phenylalanine S(Bzl) L-O-Benzylserine T(Bzl)L-O-Benzylthreonine hCha L-Homo-cyclohexylalanine hCys L-Homo-cysteinehSer L-Homo-serine hArg L-Homo-arginine hPhe L-Homo-phenylalanine BpaL-4-Benzoylphenylalanine 4-AmPyrr1(2S,4S)-4-Amino-pyrrolidine-L-carboxylic acid 4-AmPyrr2(2S,4R)-4-Amino-pyrrolidine-L-carboxylic acid 4-PhePyrr1(2S,5R)-4-Phenyl-pyrrolidine-L-carboxylic acid 4-PhePyrr2(2S,5S)-4-Phenyl-pyrrolidine-L-carboxylic acid 5-PhePyrr1(2S,5R)-5-Phenyl-pyrrolidine-L-carboxylic acid 5-PhePyrr2(2S,5S)-5-Phenyl-pyrrolidine-L-carboxylic acid 4Hyp1(4S)-L-Hydroxyproline 4Hyp2 (4R)-L-Hydroxyproline 4Mp1(4S)-L-Mercaptoproline 4Mp2 (4R)-L-Mercaptoproline Pip L-Pipecolic acidOctG L-Octylglycine NGly N-Methylglycine MePhe L-N-MethylphenylalanineMeNle L-N-Methylnorleucine MeAla L-N-Methylalanine MeIleL-N-Methylisoleucine MeVal L-N-Methylvaline MeLeu L-N-Methylleucine Hpa(2S)-2-Hydroxy-2-phenylacetic acid Ahp (2S)-3-Amino-2-hydroxy-propionicacid Ahb (2S)-4-Amino-2-hydroxy butyric acid 3Ahb(2S,3S)-3-Amino-2-hydroxy butyric acid 4Dhb (2S)-2,4-Dihydroxy butyricacid Hmcb (2S)-2-Hydroxy-4-mercapto-butyric acid Hpb(2S)-2-Hydroxy-4-phenyl-butyric acid Hcb(2S)-2-Hydroxy-4-cyclohexyl-butyric acid Hgh(2S)-2-Hydroxy-6-guanidino-hexanoic acid Hcap(2S)-2-Hydroxy-5-(carbamoylamino)pentanoic acid Ahp(2S)-5-Amino-2-hydroxy-pentanoic acid Hdmp (2S)-2-Hydroxy-4,4-dimethylpentanoic acid Hdmb (2S)-2-Hydroxy-3,3-dimethyl butyric acid Hchp(2S)-2-Hydroxy-3-cyclohexyl propionic acid Hcbp(2S)-2-Hydroxy-3-cyclobutyl propionic acid Hcpp(2S)-2-Hydroxy-3-cyclopenyl propionic acid Hca (2S)-2-Hydroxy caproicacid Hda (2S)-2-Hydroxy decanoic acid H2np(2S)-2-Hydroxy-3-(2′-naphthyl)propionic acid H1np(2S)-2-Hydroxy-3-(1′-naphthyl)propionic acid Hbp(2S)-2-Hydroxy-3-biphenyl-4′-yl propionic acid 4Clphp(2S)-3-(4′-Chlorophenyl)-2-hydroxy propionic acid 3Clphp(2S)-3-(3′-Chlorophenyl)-2-hydroxy propionic acid 2Clphp(2S)-3-(2′-Chlorophenyl)-2-hydroxy propionic acid 4Fphp(2S)-3-(4′-Fluorophenyl)-2-hydroxy propionic acid 3Fphp(2S)-3-(3′-Fluorophenyl)-2-hydroxy propionic acid 2Fphp(2S)-3-(2′-Fluorophenyl)-2-hydroxy propionic acid Aahh(2S)-6-Acetylamino-2-hydroxy-hexanoic acid Hbpp(2S)-2-Hydroxy-3-4′-benzoylphenyl propionic acid Bhp(2S)-3-Benzyloxy-2-hydroxy-propionic acid Bhb(2S,3R)-3-Benzyloxy-2-hydroxy-butyric acid Hbpp(2S)-2-Hydroxy-3-(4′-benzyloxyphenyl)- propionic acid 4Hb 4-Hydroxybutyric acid 6Hh 6-Hydroxy hexanoic acid Hib 2-Hydroxy isobutyric acid

Particularly preferred residues for group C are:

Ala L-Alanine Ile L-Isoleucine Leu L-Leucine Met L-Methionine ValL-Valine tBuA L-t-Butylalanine t-BuG L-tert.-Butylglycine ChaL-Cyclohexylalanine C₄al L-3-Cyclobutylalanine C₅alL-3-Cyclopentylalanine Nle L-Norleucine hCha L-Homo-cyclohexylalanineOctG L-Octylglycine MePhe L-N-Methylphenylalanine MeNleL-N-Methylnorleucine MeAla L-N-Methylalanine MeIle L-N-MethylisoleucineMeVal L-N-Methylvaline MeLeu L-N-Methylleucine

Particularly preferred residues for group D are:

His L-Histidine Phe L-Phenylalanine Trp L-Tryptophan Tyr L-Tyrosine PhgL-Phenylglycine 2-Nal L-2-Naphthylalanine 1-Nal L-1-Naphthylalanine4Cl-Phe L-4-Chlorophenylalanine 3Cl-Phe L-3-Chlorophenylalanine 2Cl-PheL-2-Chlorophenylalanine 3,4Cl₂-Phe L-3,4-Dichlorophenylalanine 4F-PheL-4-Fluorophenylalanine 3F-Phe L-3-Fluorophenylalanine 2F-PheL-2-Fluorophenylalanine Thi L-β-2-Thienylalanine TzaL-2-Thiazolylalanine Y(Bzl) L-O-Benzyltyrosine Bip L-BiphenylalanineS(Bzl) L-O-Benzylserine T(Bzl) L-O-Benzylthreonine hPheL-Homo-phenylalanine Bpa L-4-Benzoylphenylalanine PirrAlaL-2-(3′-pyrrolidinyl)-alanine NMePhe L-N-Methylphenylalanine 4-PyrAlaL-2-(4′Pyridyl)-alanine

Particularly preferred residues for group E are

Arg L-Arginine Lys L-Lysine Orn L-Ornithine Dpr L-2,3-Diaminopropionicacid A₂Bu L-2,4-Diaminobutyric acid Dab (2S,3S)-2,3-Diaminobutyric acidPhe(pNH₂) L-para-Aminophenylalanine Phe(mNH₂) L-meta-AminophenylalaninePhe(oNH₂) L-ortho-Aminophenylalanine hArg L-Homo-argininePhe(mC(NH₂)═NH) L-meta-Amidinophenylalanine Phe(pC(NH₂)═NH)L-para-Amidinophenylalanine Phe(mNHC(NH₂)═NH)L-meta-Guanidinophenylalanine Phe(pNHC(NH₂)═NH)L-para-Guanidinophenylalanine NMeR L-N-Methylarginine NMeKL-N-Methyllysine

Particularly preferred residues for group F are

Asn L-Asparagine Asp L-Aspartic acid Cys L-Cysteine Gln L-Glutamine^(D)Gln D-Glutamine Glu L-Glutamic acid Ser L-Serine ^(D)Ser D-SerineThr L-Threonine Cit L-Citrulline Pen L-Penicillamine AcLysL-N′-Acetyllysine hCys L-Homo-cysteine hSer L-Homo-serine

Particularly preferred residues for group L are

Lac (2S)-2-Hydroxy-propanoic acid Hmb (2S)-2-Hydroxy-3-methylbutyricacid H3mp (2S,3S)-2-Hydroxy-3-methyl-pentanoic acid H4mp(2S)-2-Hydroxy-4-methyl-pentanoic acid Hmtb (2S)-2-Hydroxy-4-methylthiobutyric acid Hhpp (2S)-2-Hydroxy-3-(4′-hydroxyphenyl)-propionic acidHimp (2S)-2-Hydroxy-3-(Imidazole-4′-yl)-propionic acid Hpp(2S)-2-Hydroxy-3-phenyl propionic acid Hinp(2S)-2-Hydroxy-3-(indol-3′-yl)-propionic acid Dhp(2S)-2,3-Dihydroxy-propionic acid Hbd (2S)-2-Hydroxybutanedioic acid Hpd(2S)-2-Hydroxy-pentanedioic acid Ahh (2S)-6-Amino-2-hydroxy-hexanoicacid Hgp (2S)-2-Hydroxy-5-guanidino-pentanoic acid Hmcp(2S)-2-Hydroxy-3-mercapto-propionic acid Haa 2-Hydroxy acetic acid Hcp2-Hydroxy-3-carbamoyl-propanoic acid Hcb 2-Hydroxy-4-carbamoyl-butanoicacid 3Dhb (2S,3R)-2,3-Dihydroxy-butyric acid Hpa(2S)-2-Hydroxy-2-phenylacetic acid Ahp (2S)-3-Amino-2-hydroxy-propionicacid Ahb (2S)-4-Amino-2-hydroxy butyric acid 3Ahb(2S,3S)-3-Amino-2-hydroxy butyric acid 4Dhb (2S)-2,4-Dihydroxy butyricacid Hmcb (2S)-2-Hydroxy-4-mercapto-butyric acid Hpb(2S)-2-Hydroxy-4-phenyl-butyric acid Hcb(2S)-2-Hydroxy-4-cyclohexyl-butyric acid Hgh(2S)-2-Hydroxy-6-guanidino-hexanoic acid Hcap2-Hydroxy-5-(carbamoylamino)pentanoic acid Ahp(2S)-5-Amino-2-hydroxy-pentanoic acid Hdmp (2S)-2-Hydroxy-4,4-dimethylpentanoic acid Hdmb (2S)-2-Hydroxy-3,3-dimethyl butyric acid Hchp(2S)-2-Hydroxy-3-cyclohexyl propionic acid Hcbp(2S)-2-Hydroxy-3-cyclobutyl propionic acid Hcpp(2S)-2-Hydroxy-3-cyclopenyl propionic acid Hca (2S)-2-Hydroxy caproicacid Hda (2S)-2-Hydroxy decanoic acid H2np(2S)-2-Hydroxy-3-(2′-naphthyl)propionic acid H1np(2S)-2-Hydroxy-3-(1′-naphthyl)propionic acid Hbp(2S)-2-Hydroxy-3-biphenyl-4′-yl propionic acid 4Clphp(2S)-3-(4′-Chlorophenyl)-2-hydroxy propionic acid 3Clphp(2S)-3-(3′-Chlorophenyl)-2-hydroxy propionic acid 2Clphp(2S)-3-(2′-Chlorophenyl)-2-hydroxy propionic acid 4Fphp(2S)-3-(4′-Fluorophenyl)-2-hydroxy propionic acid 3Fphp(2S)-3-(3′-Fluorophenyl)-2-hydroxy propionic acid 2Fphp(2S)-3-(2′-Fluorophenyl)-2-hydroxy propionic acid Aahh(2S)-6-Acetylamino-2-hydroxy-hexanoic acid Hbpp(2S)-2-Hydroxy-3-4′-benzoylphenyl propionic acid Bhp(2S)-3-Benzyloxy-2-hydroxy-propionic acid Bhb(2S,3R)-3-Benzyloxy-2-hydroxy-butyric acid Hbpp(2S)-2-Hydroxy-3-(4′-benzyloxyphenyl)-propionic acid 4Hb 4-Hydroxybutyric acid 6Hh 6-Hydroxy hexanoic acid Hib 2-Hydroxy isobutyric acid

Generally, the peptidic or depsipeptidic chain Z within the β-hairpinmimetics of the invention comprises 14 amino and/or hydroxy acidresidues. The positions P1 to P14 of each amino or hydroxy acid residuein the chain Z are unequivocally defined as follows: P1 represents thefirst amino or hydroxy acid in the chain Z that is coupled with its N-or O-terminus to the C-terminus of the templates (b)-(p), or of group-B-CO— in template (a1), or of group -A-CO— in template (a2); and P14represents the last amino or hydroxy acid in the chain Z that is coupledwith its C-terminus to the N- or O-terminus of the templates (b)-(p), orof group -A-CO— in template (a1), or of group -B-CO— in template (a2).Each of the positions P1 to P14 will contain an amino or hydroxy acidresidue belonging to one of the above types C D, E, F, H or L, or offormula -A-CO—, or being Gly or a glycolic acid residue as stated above.

The α-amino and/or α-hydroxy acid residues in positions 1 to 14 of thechain Z are preferably:

-   -   P1: of type D or of type L;    -   P2: of type D or of type L;    -   P3: of type C, type D or of type L;    -   P4: of type F;    -   P5: of type E, type F or of type L;    -   P6: of type C or of type L;    -   P7: of formula -A-CO—, Gly or Pro    -   P8: of type E or of type L;    -   P9: of type E;    -   P10: of type D;    -   P11: of type F;    -   P12: of type D or of type L;    -   P13: of type F or of type L; and    -   P14: of type E or of type L; or    -   P4 and P11, taken together, can form a group of type H;    -   at P5, P7 and P13 also D-isomers being possible.

The α-amino and/or α-hydroxy acid residues in positions 1 to 14 are mostpreferably:

-   -   P1: Tyr, Hhpp;    -   P2: His, Ahb;    -   P3: Ala, Lac;    -   P4: Cys;    -   P5: Ser, Ahb, ^(D)Ser, Arg;    -   P6: Lac, Ala;    -   P7: ^(D)Pro;    -   P8: Dab, Ahb;    -   P9: Arg;    -   P10: Tyr;    -   P11: Cys;    -   P12: Tyr, Hhpp;    -   P13: Gln, Hhpp, ^(D)Gln;    -   P14: Lys, Ahb;    -   formation of a disulfide bridge being possible between the Cys        residues at P4 and P11.

Particularly preferred β-peptidomimetics of the invention include thosedescribed in Examples 1, 3 and 7.

The processes of the invention can advantageously be carried out asparallel array syntheses to yield libraries of template-fixed β-hairpinpeptidomimetics of the above general formulae Ia or Ib. Such parallelsyntheses allow one to obtain arrays of numerous (normally 12 to 192,typically 96) compounds of general formulae Ia or Ib in moderate to highyields and defined purities, minimizing the formation of dimeric andpolymeric by-products. The proper choice of the functionalizedsolid-support (i.e. solid support plus linker molecule), templates andsite of cyclization play thereby key roles.

The functionalized solid support is conveniently derived frompolystyrene crosslinked with, preferably 1-5%, divinylbenzene;polystyrene coated with polyethyleneglycol spacers (Tentagel^(R)); andpolyacrylamide resins (see also D. Obrecht, J.-M. Villalgordo,“Solid-Supported Combinatorial and Parallel Synthesis ofSmall-Molecular-Weight Compound Libraries”, Tetrahedron OrganicChemistry Series, Vol. 17, Pergamon, Elsevier Science, 1998).

The solid support is functionalized by means of a linker, i.e. abifunctional spacer molecule which contains on one end an anchoringgroup for attachment to the solid support and on the other end aselectively cleavable functional group used for the subsequent chemicaltransformations and cleavage procedures. For the purposes of the presentinvention two types of linkers are used:

Type 1 linkers are designed to release the amide group under acidconditions (H. Rink, Tetrahedron Lett. 1987, 28, 3783-3790). Linkers ofthis kind form amides of the carboxyl group of the amino or hydroxyacids; examples of resins functionalized by such linker structuresinclude4-[(((2,4-dimethoxyphenyl)Fmoc-aminomethyl)phenoxyacetamido)aminomethyl]PS resin,4-[(((2,4-dimethoxyphenyl)Fmoc-aminomethyl)phenoxyacetamido)aminomethyl]-4-methyl-benz-hydrylaminePS resin (Rink amide MBHA PS Resin), and4-[(((2,4-dimethoxyphenyl)Fmoc-aminomethyl)phenoxyacetamido)aminomethyl]benzhydrylaminePS-resin (Rink amide BHA PS resin). Preferably, the support is derivedfrom polystyrene crosslinked with, most preferably 1-5%, divinylbenzeneand functionalized by means of the4-(((2,4-dimethoxy-phenyl)Fmoc-aminomethyl)phenoxyacetamido) linker.

Type 2 linkers are designed to eventually release the carboxyl groupunder acidic conditions. Linkers of this kind form acid-labile esterswith the carboxyl group of the amino or hydroxy acids, usuallyacid-labile benzyl, benzhydryl and trityl esters; examples of suchlinker structures include 2-methoxy-4-hydroxymethylphenoxy (Sasrin^(R)linker), 4-(2,4-di-methoxyphenyl-hydroxymethyl)-phenoxy (Rink linker),4-(4-hydroxymethyl-3-methoxyphenoxy)butyric acid (HMPB linker), trityland 2-chlorotrityl. Preferably, the support is derived from polystyrenecrosslinked with, most preferably 1-5%, divinylbenzene andfunctionalized by means of the 2-chlorotrityl linker.

When carried out as parallel array syntheses the processes of theinvention can be advantageously carried out as described herein belowbut it will be immediately apparent to those skilled in the art howthese procedures will have to be modified in case it is desired tosynthesize one single compound of the above formulae Ia or Ib.

A number of reaction vessels (normally 12 to 192, typically 96) equal tothe total number of compounds to be synthesized by the parallel methodare loaded with 25 to 1000 mg, preferably 60 mg, of the appropriatefunctionalized solid support, preferably 1 to 3% cross-linkedpolystyrene or Tentagel resin.

The solvent to be used must be capable of swelling the resin andincludes, but is not limited to, dichloromethane (DCM),dimethylformamide (DMF), N-methylpyrrolidone (NMP), dioxane, toluene,tetrahydrofuran (THF), ethanol (EtOH), trifluoroethanol (TFE),isopropylalcohol and the like. Solvent mixtures containing as at leastone component a polar solvent (e. g. 20% TFE/DCM, 35% THF/NMP) arebeneficial for ensuring high reactivity and solvation of the resin-boundpeptide chains (G. B. Fields, C. G. Fields, J. Am. Chem. Soc. 1991, 113,4202-4207).

With the development of various linkers that release the C-terminalcarboxylic acid group under mild acidic conditions, not affectingacid-labile groups protecting functional groups in the side chain(s),considerable progresses have been made in the synthesis of protectedpeptide fragments. The 2-methoxy-4-hydroxybenzylalcohol-derived linker(Sasrin^(R) linker, Mergler et al., Tetrahedron Lett. 1988, 294005-4008) is cleavable with diluted trifluoroacetic acid (0.5-1% TFA inDCM) and is stable to Fmoc deprotection conditions during the peptidesynthesis, Boc/tBu-based additional protecting groups being compatiblewith this protection scheme. Other linkers which are suitable for theprocess of the invention include the super acid labile4-(2,4-dimethoxyphenyl-hydroxymethyl)-phenoxy linker (Rink linker, H.Rink, Tetrahedron Lett. 1987, 28, 3787-3790), where the removal of thedepsipeptide requires 10% acetic acid in DCM or 0.2% trifluoroaceticacid in DCM; the 4-(4-hydroxymethyl-3-methoxyphenoxy)butyricacid-derived linker (HMPB-linker, Flörsheimer & Riniker, Peptides 1991,1990 131) which is also cleaved with 1% TFA/DCM in order to yield apeptide fragment containing all acid labile side-chain protectivegroups; and, in addition, the 2-chlorotritylchloride linker (Barlos etal., Tetrahedron Lett. 1989, 30, 3943-3946), which allows thedepsipeptide detachment using a mixture of glacial aceticacid/trifluoroethanol/DCM (1:2:7) for 30 min.

Suitable protecting groups for amino or hydroxy acids and, respectively,for their residues are, for example,

-   -   for the amino group (as is present e. g. also in the side-chain        of lysine)

Cbz benzyloxycarbonyl Boc tert.-butyloxycarbonyl Fmoc9-fluorenylmethoxycarbonyl Alloc allyloxycarbonyl Teoctrimethylsilylethoxycarbonyl Tcc trichloroethoxycarbonyl Npso-nitrophenylsulfonyl; Trt triphenymethyl or trityl

-   -   for the carboxyl group (as is present e. g. also in the        side-chain of aspartic and glutamic acid) by conversion into        esters with the alcohol components

tBu tert.-butyl Bn benzyl Me methyl Ph phenyl Pac phenacyl allyl Tsetrimethylsilylethyl Tce trichloroethyl;

-   -   for the guanidino group (as is present e. g. in the side-chain        of arginine)

Pmc 2,2,5,7,8-pentamethylchroman-6-sulfonyl Ts tosyl (i.e.p-toluenesulfonyl) Cbz benzyloxycarbonyl Pbfpentamethyldihydrobenzofuran-5-sulfonyl

-   -   for the hydroxy group (as is present e. g. in the side-chain of        threonine and serine)

tBu tert.-butyl Bn benzyl Trt trityl Alloc allyloxycarbonyl

-   -   and for the mercapto group (as is present e. g. in the        side-chain of cysteine)

Acm acetamidomethyl tBu tert.-butyl Bn benzyl Trt trityl Mtr4-methoxytrityl.

The 9-fluorenylmethoxycarbonyl-(Fmoc)-protected amino acid derivativesare preferably used as the building blocks for the construction of thetemplate-fixed β-hairpin loop mimetics of formulae Ia or Ib. For thedeprotection, i. e. cleaving off of the Fmoc group, 20% piperidine inDMF or 2% DBU/2% piperidine in DMF can be used.

The quantity of the reactant, i. e. of the amino or hydroxy acidderivative, is usually 1 to 20 equivalents based on the milliequivalentsper gram (meq/g) loading of the functionalized solid support (typically0.1 to 2.85 meq/g for polystyrene resins) originally weighed into thereaction tube. Additional equivalents of reactants can be used, ifrequired, to drive the reaction to completion in a reasonable time. Thepreferred workstations (without, however, being limited thereto) areLabsource's Combi-chem station, Protein Technologies' Symphony andMultiSyn Tech's-Syro synthesizer, the latter additionally equipped witha transfer unit and a reservoir box during the process of detachment ofthe fully protected linear peptide from the solid support. Allsynthesizers are able to provide a controlled environment, for example,reactions can be accomplished at temperatures different from roomtemperature as well as under inert gas atmosphere, if desired.

Amide bond formation requires the activation of the α-carboxyl group forthe acylation step. When this activation is being carried out by meansof the commonly used carbodiimides such as dicyclohexylcarbodiimide(DCC, Sheehan & Hess, J. Am. Chem. Soc. 1955, 77, 1067-1068) ordiisopropylcarbodiimide (DIC, Sarantakis et al Biochem. Biophys. Res.Commun. 1976, 73, 336-342), the resulting dicyclohexylurea and,respectively, diisopropylurea is insoluble and, respectively, soluble inthe solvents generally used. In a variation of the carbodiimide method1-hydroxybenzotriazole (HOBt, Konig & Geiger, Chem. Ber. 1970, 103,788-798) is included as an additive to the coupling mixture. HOBtprevents dehydration, suppresses racemization of the activated aminoacids and acts as a catalyst to improve the sluggish coupling reactions.Certain phosphonium reagents have been used as direct coupling reagents,such as benzotriazol-1-yl-oxy-tris-(dimethyl-amino)-phosphoniumhexafluorophosphate (BOP, Castro et al., Tetrahedron Lett. 1975, 14,1219-1222; Synthesis 1976, 751-752), orbenzotriazol-1-yl-oxy-tris-pyrrolidino-phosphonium hexaflurophoshate(Py-BOP, Coste et al., Tetrahedron Lett. 1990, 31, 205-208), or2-(1H-benzotriazol-1-yl-)1,1,3,3-tetramethyluronium tetrafluoroborate(TBTU), or hexafluorophosphate (HBTU, Knorr et al., Tetrahedron Lett.1989, 30, 1927-1930); these phosphonium reagents are also suitable forin situ formation of HOBt esters with the protected amino acidderivatives. More recently diphenoxyphosphoryl azide (DPPA) orO-(7-aza-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumtetrafluoroborate (TATU) orO-(7-aza-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU)/7-aza-1-hydroxy benzotriazole (HOAt, Carpinoet al., Tetrahedron Lett. 1994, 35, 2279-2281) or-(6-Chloro-1H-benzotriazol-1-yl-)-N,N,N′,N′-1,1,3,3-tetramethyluroniumtetrafluoroborate (TCTU), or hexafluorophosphate (HCTU, Marder, Shivoand Albericio: HCTU and TCTU: New Coupling Reagents: Development andIndustrial Applications, Poster Presentation, Gordon Conference February2002) have also been used as coupling reagents.

Ester bond formation, or more precisely, the acylation of the α-hydroxygroup requires more potent carboxyl-activating reagents than describedabove. Activation with DIC in the presence of 4-Dimethylaminopyridine(DMAP, J. W. Blankenship et al., Biochemistry, 2002, 41, 15676-15684) orthe generation of the symmetric anhydride in the presence of DMAP (E.Bianchi et al., Anal. Biochem., 1996, 237, 329-244) or the use of1-(2-mesitylenesulfonyl)-3-nitro-1,2,4-triazole (MSNT) in the presenceof N-methylimidazole (NMI) and DIEA (L. J. Cruz et al., J. Org. Chem.,2006, 71, 3339-3344) have been described.

Due to the fact that near-quantitative coupling reactions are essential,it is desirable to have experimental evidence for completion of thereactions. The ninhydrin test (Kaiser et al., Anal. Biochemistry 1970,34, 595), where a positive colorimetric response to an aliquot ofresin-bound peptide or depsipeptide indicates qualitatively the presenceof the primary amine, can easily and quickly be performed after eachcoupling step. Fmoc chemistry allows the spectrophotometric detection ofthe Fmoc chromophore when it is released with the base (Meienhofer etal., Int. J. Peptide Protein Res. 1979, 13, 35-42).

The resin-bound intermediate within each reaction vessel is washed freeof excess of retained reagents, of solvents, and of by-products byrepetitive exposure to pure solvent(s) by one of the two followingmethods:

1) The reaction vessels are filled with solvent (preferably 5 ml),agitated for 5 to 300 minutes, preferably 15 minutes, and drained toexpel the solvent;

2) The reaction vessels are filled with solvent (preferably 5 ml) anddrained into a receiving vessel such as a test tube or vial.

Both of the above washing procedures are repeated up to about 50 times(preferably about 10 times), monitoring the efficiency of reagent,solvent, and by-product removal by methods such as TLC, GC, orinspection of the washings.

The above described procedure of reacting the resin-bound compound withreagents within the reaction tubes followed by removal of excessreagents, by-products, and solvents is repeated with each successivetransformation until the final resin-bound fully protected lineardepsipeptide has been obtained.

Before this fully protected linear peptide or depsipeptide is detachedfrom the solid support, it is possible, if desired, to selectivelydeprotect one or several protected functional group(s) present in themolecule and to appropriately substitute the reactive group(s) thusliberated. To this effect, the functional group(s) in question mustinitially be protected by a protecting group which can be selectivelyremoved without affecting the remaining protecting groups present. Alloc(allyloxycarbonyl) is an example for such an amino protecting groupwhich can be selectively removed, e.g. by means of Pd⁰ and phenylsilanein CH₂Cl₂, without affecting the remaining protecting groups, such asFmoc, present in the molecule. The reactive group thus liberated canthen be treated with an agent suitable for introducing the desiredsubstituent. Thus, for example, an amino group can be acylated by meansof an acylating agent corresponding to the acyl substituent to beintroduced.

Before this fully protected linear peptide or depsipeptide is detachedfrom the solid support, it is also possible, if desired, to form aninterstrand linkages between side-chains of appropriate amino residuesat positions P4 and P11.

Interstrand linkages and their formation have been discussed above, inconnection with the explanations made regarding groups of the type Hwhich can, for example, be disulfide bridges formed by cysteine andhomocysteine residues at opposite positions of the β-strand; or lactambridges formed by glutamic and aspartic acid residues linking ornithineand, respectively, lysine residues, or by glutamic acid residues linking2,4-diaminobutyric acid residues located at opposite β-strand positionsby amide bond formation. The formation of such interstrand linkages canbe effected by methods well known in the art.

For the formation of disulfide bridges preferably a solution of 10equivalents of iodine solution is applied in DMF or in a mixture ofCH₂Cl₂/MeOH for 1.5 h which is repeated for another 3 h with a freshiodine solution after filtering of the iodine solution, or in a mixtureof DMSO and acetic acid solution, buffered with 5% with NaHCO₃ to pH 5-6for 4 h, or in water after adjusting to pH 8 with ammonium hydroxidesolution by stirring for 24 h, or in a solution of NMP andtri-n-butylphosphine (preferably 50 eq.).

For the formation of lactam bridges preferably a solution of 2equivalents of HATU (N-[(dimethylamino)-1H-1,2,3-triazolo[4,5-b]pyridin-1-ylmethylene)-N-methylmethanaminium hexa-fluorophosphateN-oxide) in dry DMF and a solution of 4 equivalents of DIPEA(Diisopropyl ethylamine) in dry DMF is applied for 16 h.

Detachment of the fully protected linear peptide or depsipeptide fromthe solid support is achieved by exposing the loaded resin with asolution of the cleavage reagent (preferably 3 to 5 ml). Temperaturecontrol, agitation, and reaction monitoring are implemented as describedabove. Via a transfer-unit the reaction vessels are connected with areservoir box containing reservoir tubes to efficiently collect thecleaved product solutions. The resins remaining in the reaction vesselsare then washed 2 to 5 times as above with 3 to 5 ml of an appropriatesolvent to extract (wash out) as much of the detached products aspossible. The product solutions thus obtained are combined, taking careto avoid cross-mixing. The individual solutions/extracts are thenmanipulated as needed to isolate the final compounds. Typicalmanipulations include, but are not limited to, evaporation,concentration, liquid/liquid extraction, acidification, basification,neutralization or additional reactions in solution.

The solutions containing fully protected linear peptide or depsipeptidederivatives which have been cleaved off from the solid support andneutralized with a base, are evaporated to dryness. Cyclization is theneffected in solution using solvents such as DCM, DMF, dioxane, THF andthe like. Various coupling reagents which were mentioned earlier can beused for the cyclization. The duration of the cyclization is about 6-48hours, preferably about 16 hours. The progress of the reaction isfollowed, e. g. by RP-HPLC (Reverse Phase High Performance LiquidChromatography). Then the solvent is removed by evaporation, the fullyprotected cyclic depsipeptide derivative is dissolved in a solvent whichis not miscible with water, such as DCM, and the solution is extractedwith water or a mixture of water-miscible solvents, in order to removeany excess of the coupling reagent.

Alternatively, the detachment and complete deprotection of the fullyprotected peptide or depsipeptide from the solid support can be achievedmanually in glass vessels.

Finally, the fully protected depsipeptide derivative is treated with 95%TFA, 2.5% H₂O, 2.5% TIS or another combination of scavengers foreffecting the cleavage of protecting groups. The cleavage reaction timeis commonly 30 minutes to 12 hours, preferably about 2.5 hours.

After full deprotection one of the following methods can be used forfurther work-up:

1) The solutions are evaporated to dryness and the crude peptide isdissolved in 20% AcOH in water and extracted with isopropyl ether orother solvents which are suitable therefor. The aqueous layer iscollected and evaporated to dryness, and the fully deprotecteddepsipeptide derivative of formula Ia or Ib is obtained as end-product;

2) The deprotection mixture is concentrated under vacuum. Followingprecipitation of the fully deprotected depsipeptide in diethylether atpreferably 0° C. the solid is washed up to about 10 times, preferably 3times, dried, and the the fully deprotected depsipeptide derivative offormula Ia or Ib is obtained as end-product.

As mentioned earlier, it is thereafter possible, if desired, to converta fully deprotected product of formula Ia or Ib thus obtained into apharmaceutically acceptable salt or to convert a pharmaceuticallyacceptable, or unacceptable, salt thus obtained into the correspondingfree compound of formula Ia or Ib or into a different, pharmaceuticallyacceptable, salt. Any of these operations can be carried out by methodswell known in the art.

The template starting materials of formula IIa used in the processes ofthe invention, pre-starting materials therefore, and the preparation ofthese starting and pre-starting materials are described in InternationalApplication PCT/EP02/01711 of the same applicants, published as WO02/070547 A1.

The β-hairpin peptidomimetics of the invention can be used in a widerange of applications in order to prevent HIV infections in non-infectedindividuals and slow or halt viral progression in infected patients, orwhere cancer is mediated or resulting from the CXCR4 receptor activity,or where immunological diseases are mediated or resulting from CXCR4receptor activity; or the β-hairpin peptidomimetics of the invention canbe used to treat immuno supersession, or they can be used duringapheresis collections of peripheral blood stem cells and/or as agents toinduce mobilization of stem cells to regulate tissue repair.

The β-hairpin peptidomimetics may be administered per se or may beapplied as an appropriate formulation together with carriers, diluentsor excipients well known in the art.

When used to treat or prevent HIV infections or cancer such as breastcancer, brain cancer, prostate cancer, lung cancer, kidney cancer,neuroblastoma, non-hodgkin's lymphoma, ovarian cancer, eye cancer,multiple myeloma, chronic lyphomphocytic leukemia, pancreatic cancer,melanoma, angiogenesis, and haematopoetic tissues; or inflammatorydisorders such as asthma, allergic rhinitis, hypersensitivity lungdiseases, hypersensitivity pneumonitis, eosinophilic pneumonias,delayed-type hypersensitivity, interstitial lung diseas (ILD),idiopathic pulmonary fibrosis, ILD associated with rheumatoid arthritis,systemic lupus erythematosus, ankylosing sponylitis, systemic sclerosis,Sjogren's syndrome, systemic anaphylaxis or hypersensitivity responses,drug allergies, rheumatoid arthritis, psoriatic arthritis, systemiclupus erythematosus, myasthenia gravis, juvenile onset diabetes,glomerulonephritis, autoimmune throiditis, graft rejection, includingallograft rejection or graft-versus-host disease, inflammatory boweldiseases, inflammatory dermatoses; or to treat glaucoma; or to treatfocal ischemic stroke, global cerebral ischemia, myocardial infarction,hind limb ischemia and peripheral ischemia; or to treat injury of theliver, kidney and lung or to treat immunosuppression, includingimmunosuppression induced by chemotherapy, radiation therapy orgraft/transplantation rejection, the β-hairpin peptidomimetics can beadministered singly, as mixtures of several β-hairpin peptidomimetics,in combination with other anti-HIV agents, or antimicrobial agents oranti cancer agents or anti-inflammatory agents, or in combination withother pharmaceutically active agents. The β-hairpin peptidomimetics canbe administered per se or as pharmaceutical compositions.

Pharmaceutical compositions comprising n-hairpin peptidomimetics of theinvention may be manufactured by means of conventional mixing,dissolving, granulating, coated tablet-making, levigating, emulsifying,encapsulating, entrapping or lyophilizing processes. Pharmaceuticalcompositions may be formulated in conventional manner using one or morephysiologically acceptable carriers, diluents, excipients orauxilliaries which facilitate processing of the active β-hairpinpeptidomimetics into preparations which can be used pharmaceutically.Proper formulation depends upon the method of administration chosen.

For topical administration the β-hairpin peptidomimetics of theinvention may be formulated as solutions, gels, ointments, creams,suspensions, etc. as are well-known in the art.

Systemic formulations include those designed for administration byinjection, e.g. subcutaneous, intravenous, intramuscular, intrathecal orintraperitoneal injection, as well as those designed for transdermal,transmucosal, oral or pulmonary administration.

For injections, the β-hairpin peptidomimetics of the invention may beformulated in adequate solutions, preferably in physiologicallycompatible buffers such as Hink's solution, Ringer's solution, orphysiological saline buffer. The solutions may contain formulatoryagents such as suspending, stabilizing and/or dispersing agents.Alternatively, the β-hairpin peptidomimetics of the invention may be inpowder form for combination with a suitable vehicle, e.g., sterilepyrogen-free water, before use.

For transmucosal administration, penetrants appropriate to the barrierto be permeated are used in the formulation as known in the art.

For oral administration, the compounds can be readily formulated bycombining the active β-hairpin peptidomimetics of the invention withpharmaceutically acceptable carriers well known in the art. Suchcarriers enable the β-hairpin peptidomimetics of the invention to beformulated as tablets, pills, dragees, capsules, liquids, gels, syrups,slurries, suspensions etc., for oral ingestion by a patient to betreated. For oral formulations such as, for example, powders, capsulesand tablets, suitable excipients include fillers such as sugars, such aslactose, sucrose, mannitol and sorbitol; cellulose preparations such asmaize starch, wheat starch, rice starch, potato starch, gelatin, gumtragacanth, methyl cellulose, hydroxypropylmethyl cellulose, sodiumcarboxymethylcellulose, and/or polyvinylpyrrolidone (PVP); granulatingagents; and binding agents. If desired, desintegrating agents may beadded, such as cross-linked polyvinylpyrrolidones, agar, or alginic acidor a salt thereof, such as sodium alginate. If desired, solid dosageforms may be sugar-coated or enteric-coated using standard techniques.

For oral liquid preparations such as, for example, suspensions, elixirsand solutions, suitable carriers, excipients or diluents include water,glycols, oils, alcohols, etc. In addition, flavoring agents,preservatives, coloring agents and the like may be added.

For buccal administration, the composition may take the form of tablets,lozenges, etc. formulated as usual.

For administration by inhalation, the β-hairpin peptido-mimetics of theinvention are conveniently delivered in form of an aeorosol spray frompressurized packs or a nebulizer, with the use of a suitable propellant,e.g. dichlorodifluoromethane, trichiorofluromethane, carbon dioxide oranother suitable gas. In the case of a pressurized aerosol the dose unitmay be determined by providing a valve to deliver a metered amount.Capsules and cartridges of e.g. gelatin for use in an inhaler orinsufflator may be formulated containing a powder mix of the β-hairpinpeptidomimetics of the invention and a suitable powder base such aslactose or starch.

The compounds may also be formulated in rectal or vaginal compositionssuch as suppositories together with appropriate suppository bases suchas cocoa butter or other glycerides.

In addition to the formulations described previously, the β-hairpinpeptidomimetics of the invention may also be formulated as depotpreparations. Such long acting formulations may be administered byimplantation (e.g. subcutaneously or intramuscularly) or byintramuscular injection. For the manufacture of such depot preparationsthe β-hairpin peptidomimetics of the invention may be formulated withsuitable polymeric or hydrophobic materials (e.g. as an emulsion in anacceptable oil) or ion exchange resins, or as sparingly soluble salts.

In addition, other pharmaceutical delivery systems may be employed suchas liposomes and emulsions well known in the art. Certain organicsolvents such as dimethylsulfoxide may also be employed. Additionally,the β-hairpin peptidomimetics of the invention may be delivered using asustained-release system, such as semipermeable matrices of solidpolymers containing the therapeutic agent. Various sustained-releasematerials have been established and are well known by those skilled inthe art. Sustained-release capsules may, depending on their chemicalnature, release the compounds for a few weeks up to over 100 days.Depending on the chemical nature and the biological stability of thetherapeutic agent, additional strategies for protein stabilization maybe employed.

As the β-hairpin pepdidomimetics of the invention may contain chargedresidues, they may be included in any of the above-describedformulations as such or as pharmaceutically acceptable salts.Pharmaceutically acceptable salts tend to be more soluble in aqueous andother protic solvents than are the corresponding free forms.

The β-hairpin peptidomimetics of the invention, or compositions thereof,will generally be used in an amount effective to achieve the intendedpurpose. It is to be understood that the amount used will depend on aparticular application.

For topical administration to treat or prevent HIV infections atherapeutically effective dose can be determined using, for example, thein vitro assays provided in the examples. The treatment may be appliedwhile the HIV infection is visible, or even when it is not visible. Anordinary skilled expert will be able to determine therapeuticallyeffective amounts to treat topical HIV infections without undueexperimentation.

For systemic administration, a therapeutically effective dose can beestimated initially from in vitro assays. For example, a dose can beformulated in animal models to achieve a circulating β-hairpinpeptidomimetic concentration range that includes the IC₅₀ as determinedin the cell culture (i.e. the concentration of a test compound that islethal to 50% of a cell culture). Such information can be used to moreaccurately determine useful doses in humans.

Initial dosages can also be determined from in vivo data, e.g. animalmodels, using techniques that are well known in the art. One havingordinary skill in the art could readily optimize administration tohumans based on animal data.

Dosage amounts for applications as anti-HIV agents may be adjustedindividually to provide plasma levels of the β-hairpin peptidomimeticsof the invention which are sufficient to maintain the therapeuticeffect. Therapeutically effective serum levels may be achieved byadministering multiple doses each day.

In cases of local administration or selective uptake, the effectivelocal concentration of the β-hairpin peptido-mimetics of the inventionmay not be related to plasma concentration. One having the ordinaryskill in the art will be able to optimize therapeutically effectivelocal dosages without undue experimentation.

The amount of β-hairpin peptidomimetics administered will, of course, bedependent on the subject being treated, on the subject's weight, theseverity of the affliction, the manner of administration and thejudgement of the prescribing physician.

The anti-HIV therapy may be repeated intermittently while infections aredetectable or even when they are not detectable. The therapy may beprovided alone or in combination with other drugs, such as for exampleother anti-HIV agents or anti cancer agents, or other antimicrobialagents.

Normally, a therapeutically effective dose of the β-hairpinpeptidomimetics described herein will provide therapeutic benefitwithout causing substantial toxicity.

Toxicity of the β-hairpin peptidomimetics of the invention can bedetermined by standard pharmaceutical procedures in cell cultures orexperimental animals, e.g., by determining the LD₅₀ (the dose lethal to50% of the population) or the LD₁₀₀ (the dose lethal to 100% of thepopulation). The dose ratio between toxic and therapeutic effect is thetherapeutic index. Compounds which exhibit high therapeutic indices arepreferred. The data obtained from these cell culture assays and animalstudies can be used in formulating a dosage range that is not toxic foruse in humans. The dosage of the β-hairpin peptidomimetics of theinvention lies preferably within a range of circulating concentrationsthat include the effective dose with little or no toxicity. The dosagemay vary within the range depending upon the dosage form employed andthe route of administration utilized. The exact formulation, route ofadministration and dose can be chosen by the individual physician inview of the patient's condition (see, e.g. Fingl et al. 1975, In: ThePharmacological Basis of Therapeutics, Ch. 1, p. 1).

The following Examples illustrate the present invention but are not tobe construed as limiting its scope in any way.

EXAMPLES

1. Depsipeptide Synthesis

Coupling of the First Protected amino or hydroxy acid Residue to theResin

1 g (1.4 mMol) of 2-chlorotritylchloride resin (1.4 mMol/g; Barlos etal. Tetrahedron Lett. 1989, 30, 3943-3946) was filled into a driedflask. The resin was suspended in CH₂Cl₂ (5 ml) and allowed to swell atroom temperature under constant shaking for 30 min. A solution of 0.98mMol (0.7 eq) of the first suitably protected amino acid residue (seebelow) in CH₂Cl₂ (5 ml) completed by 960 μl (4 eq) ofdiisopropylethylamine (DIEA) was added. After shaking the reactionmixture for 4 hours at 25° C. the resin was filtered off and washedsuccessively with CH₂Cl₂ (1×), DMF (1×) and CH₂Cl₂ (1×). A solution ofCH₂Cl₂/MeOH/DIEA (17/2/1, 10 ml) was added to the resin and thesuspension was shaken for 30 min. After filtration the resin was washedin the following order with CH₂Cl₂ (1×), DMF (1×), CH₂Cl₂ (1×), MeOH(1×), CH₂Cl₂ (1×) , MeOH (1×), CH₂Cl₂ (2×), Et₂O (2×) and dried undervacuum for 6 hours.

Loading was typically 0.6-0.7 mMol/g.

The following preloaded resins were prepared:Fmoc-Dab(Boc)O-chlorotrityl resin, Fmoc-AlaO-chlorotrityl resin,Fmoc-Tyr(tBu)O-chlorotrityl resin, Fmoc-ProO-chlorotrityl resin,Fmoc-DProO-chlorotritylresin and Fmoc-Arg(Pbf)O-chlorotrityl resin.

The synthesis was carried out employing a Symphony-peptide synthesizer(Protein Technologies Inc.) using 1-12 reaction vessels. In each vessel0.2 mMol of the above resin were placed and the resin was swollen inCH₂Cl₂ and DMF for 15 min, respectively. The following reaction cycleswere programmed and carried out:

Step Reagent Time 1 DMF, wash 2 × 1.5 min 2 20% piperidine/DMF 1 × 2min, 1 × 5 min 3 DMF, wash 5 × 1.5 min  4a 3.7 eq Fmoc amino acid/DMF + 1 × 40 min 3.7 eq HCTU, 7.5 eq DIEA/DMF 5 DMF, wash 3 × 1.5 min 6 4.4eq Z-(2Cl)-OSu,   1 × 8 min 8.7 eq DIEA in NMP/CH₂Cl₂ 7 DMF, wash   2 ×3 min

Step 4a was repeated once.

Unless indicated otherwise, the final coupling of an amino acid wasfollowed by a Fmoc deprotection by applying steps 1-3 of the abovedescribed reaction cycle.

To introduce an α-hydroxy acid into specific positions within the chain,step 4b was used instead of step 4a:

4b 5 eq α-hydroxy acid

-   -   +5 eq HOBt/DMF +5.5 eq DIC 1×6 h

The reaction cycle was finished by skipping steps 6 and 7.

Moreover, if an α-hydroxy acid had been introduced in the previouscycle, step 4a was modified as follows:

4c 5 eq Fmoc amino acid

-   -   +0.25 eq DMAP/CH₂Cl₂+5.5 eq DIC 1×4 h at 0° C.

Finally, His was always incorporated into the chain by using step 4dinstead of 4a:

4d 5 eq Fmoc-His(Trt)-OH+

-   -   5 eq HOBt/DMF +5.5 eq DIC 1×6 h

The following side-chain protected α-hydroxy acid derivatives had to besynthesized before their usage in the linear depsipeptide synthesisdescribed above:

N-Boc-protected (2S)-4-amino-2-hydroxybutyric acid was synthesized by aprocedure following J. Vizzavona, M. Villain, K. Rose, Tetrahedron Lett.2002, 43, 8693-8696). The synthesis of(2S)-β-(4-[benzyloxy]phenyl)lactic acid was carried out following N.Valls, M. Lopez-Canet, M. Vallribera, J. Bonjoch, Chem. Eur. J. 2001, 7,3446-3460)

Cyclization and Work Up of Backbone Cyclized Depsipeptides

Cleavage of the Fully Protected Depsipeptide Fragment

After completion of the synthesis, the resin (0.2 mMol) was suspended in5 ml (0.67 mMol, 3.4 eq) of 1% TFA in CH₂Cl₂ (v/v) for 3 minutes,filtered, and the filtrate was neutralized with 5 ml (2.92 mMol, 14.6eq) of 10% DIEA in CH₂Cl₂ (v/v). This procedure was repeated three timesto ensure completion of the cleavage. The filtrate was evaporated todryness and a sample of the product was fully deprotected by using acleavage mixture containing 95% trifluoroacetic acid (TFA), 2.5% waterand 2.5% triisopropylsilane (TIS) to be analyzed by reverse phase-HPLC(column C₁₈) and ESI-MS to monitor the efficiency of the lineardepsipeptide synthesis.

Cyclization of the Linear Depsipeptide

The fully protected linear depsipeptide (0.2 mMol) was dissolved in DMF(4 μMol/ml). Then 152.1 mg (0.4 mMol, 2 eq) of HATU, 54.4 mg (0.4 mMol,2 eq) of HOAt and 137 μl (0.8 mMol, 4 eq) DIEA were added, and themixture was vortexed at 25° C. for 16 hours and subsequentlyconcentrated under high vacuum. The residue was partitioned betweenCH₂Cl₂ and H₂O/CH₃CN (90/10: v/v). The CH₂Cl₂ phase was evaporated toyield the fully protected cyclic depsipeptide.

Full Deprotection of the Cyclic Depsipeptide

The cyclic depsipeptide obtained was dissolved in 15 ml of the cleavagemixture containing 82.5% trifluoroacetic acid (TFA), 5% water, 5%thioanisole, 5% phenol and 2.5% ethandithiole (EDT). The mixture wasallowed to stand at 25° C. for 2.5 hours and thereafter concentratedunder vacuum. After precipitation of the cyclic fully deprotecteddepsipeptide in diethylether (Et₂O) at 0° C. the solid was washed twicewith Et₂O and dried.

Formation of Disulfide β-Strand Linkage and Purification

After full deprotection, the crude depsipeptide was dissolved in 0.1 Mammonium acetate buffer (1 mg/1 ml, pH=7-8). DMSO (up to 5% by volume)was added and the solution was shaken overnight. Following evaporationthe residue was purified by preparative reverse phase HPLC.

Analytical Method 1:

Analytical HPLC retention times (RT, in minutes) were determined usingan Acquity UPLC BEH C18 1.7 μm column with the following solvents A(H₂O/CH₃CN, 95/5 [v/v], +0.1% TFA) and B (CH₃CN+0.09% TFA) and thegradient: 0 min: 99% A, 1% B; 4 min: 35% A, 65% B; 4.05-4.2 min: 5% A,95% B; 4.25-4.5 min: 99% A, 1% B.

Analytical Method 2:

Analytical HPLC retention times (RT, in minutes) were determined usingan Acquity UPLC BEH C18 1.7 μm column with the following solvents A(H₂O+0.1% TFA) and B (CH₃CN+0.09% TFA) and the gradient: 0 min: 99% A,1% B; 0.2 min: 99% A, 1% B; 2.5 min: 35% A, 65% B; 2.55-2.7 min:1% A,99% B; 2.75-3.2 min: 99% A, 1% B.

Examples 1 and 7 are shown in Table 1. The depsipeptides weresynthesized starting with the amino acid Dab which was grafted to theresin. Starting resin was Fmoc-Dab(Boc)O-chlorotrityl resin, which wasprepared as described above. The linear depsipeptides were synthesizedon solid support according to the procedure described above in thefollowing sequence:Resin-Dab(Boc)-P7-P6-P5-P4-P3-P2-P1-Pro-^(D)Pro-P14-P13-P12-P11-P10-P9.Following a final Fmoc deprotection as described above, thedepsipeptides were cleaved from the resin, cyclized, deprotected andafter formation of the disulfide β-strand linkage purified as indicatedabove.

HPLC-retention times (minutes) were determined using the gradient method1 as described above

Example 2 is shown in Table 1, too. The depsipeptide was synthesizedstarting with the amino acid Ala which was grafted to the resin.Starting resin was Fmoc-AlaO-chlorotrityl resin, which was prepared asdescribed above. The linear depsipeptide was synthesized on solidsupport according to the procedure described above in the followingsequence:Resin-Ala-P5-P4-P3-P2-P1-Pro-^(D)Pro-P14-P13-P12-P11-P10-P9-P8-P7.Following a final Fmoc deprotection as described above, the depsipeptidewas cleaved from the resin, cyclized, deprotected and after formation ofthe disulfide β-strand linkage purified as indicated above.

HPLC-retention time (minutes) was determined using the gradient method 2as described above

Example 3 is likewise shown in Table 1. The depsipeptide was synthesizedstarting with the amino acid Tyr which was grafted to the resin.Starting resin was Fmoc-Tyr(tBu)O-chlorotrityl resin, which was preparedas described above. The linear depsipeptide was synthesized on solidsupport according to the procedure described above in the followingsequence:Resin-Tyr(tBu)-P9-P8-P7-P6-P5-P4-P3-P2-P1-Pro-^(D)Pro-P14-P13-P12-P11.Following a final Fmoc deprotection as described above, the depsipeptidewas cleaved from the resin, cyclized, deprotected and after formation ofthe disulfide β-strand linkage purified as indicated above.

HPLC-retention time (minutes) was determined using the gradient method 1as described above

Examples 4, 6, 8 and 10 are shown in Table 1 as well. The depsipeptideswere synthesized starting with the amino acid Pro which was grafted tothe resin. Starting resin was Fmoc-ProO-chlorotrityl resin, which wasprepared as described above. The linear depsipeptides were synthesizedon solid support according to the procedure described above in thefollowing sequence:Resin-Pro-^(D)Pro-P14-P13-P12-P11-P10-P9-P8-P7-P6-PS-P4-P3-P2-P1.Following a final Fmoc deprotection as described above, thedepsipeptides were cleaved from the resin, cyclized, deprotected andafter formation of the disulfide β-strand linkage purified as indicatedabove.

HPLC-retention times (minutes) were determined using the gradient method1 as described above

Example 5 is also shown in Table 1. The depsipeptide was synthesizedstarting with the amino acid ^(D)Pro which was grafted to the resin.Starting resin was Fmoc-^(D)ProO-chlorotrityl resin, which was preparedas described above. The linear depsipeptide was synthesized on solidsupport according to the procedure described above in the followingsequence:Resin-^(D)Pro-P14-P13-P12-P11-P10-P9-P8-P7-P6-P5-P4-P3-P2-P1-Pro.Following a final Fmoc deprotection as described above, the depsipeptidewas cleaved from the resin, cyclized, deprotected and after formation ofthe disulfide β-strand linkage purified as indicated above.

HPLC-retention time (minutes) was determined using the gradient method 1as described above

Example 9 is also shown in Table 1. The depsipeptide was synthesizedstarting with the amino acid Arg which was grafted to the resin.Starting resin was Fmoc-Arg(Pbf)O-chlorotrityl resin, which was preparedas described above. The linear depsipeptide was synthesized on solidsupport according to the procedure described above in the followingsequence:Resin-Arg-P4-P3-P2-P1-Pro-^(D)Pro-P14-P13-P12-P11-P10-P9-P8-P7-P6.Following a final Fmoc deprotection as described above, the depsipeptidewas cleaved from the resin, cyclized, deprotected and after formation ofthe disulfide β-strand linkage purified as indicated above.

HPLC-retention time (minutes) was determined using the gradient method 1as described above.

TABLE 1 Examples (Ex.) Pur. [M + Ex. Seq ID P1 P2 P3 P4 P5 P6 P7 P8 P9P10 P11 P12 P13 P14 Template %^(a)) 2H]/2 RT 1. SEQ ID Tyr His Ala CysSer Lac ^(D)Pro Dab Arg Tyr Cys Tyr Gln Lys ^(D)Pro^(L)Pro 95 933.0 1.84NO: 1 2. SEQ ID Tyr His Ala Cys Ser Ala ^(D)Pro Ahb Arg Tyr Cys Tyr GlnLys ^(D)Pro^(L)Pro 95 932.9 1.71 NO: 2 3. SEQ ID Tyr His Ala Cys Ser Ala^(D)Pro Dab Arg Tyr Cys Hhpp Gln Lys ^(D)Pro^(L)Pro 85 932.7 1.86 NO: 34. SEQ ID Tyr His Ala Cys Ser Ala ^(D)Pro Dab Arg Tyr Cys Tyr Hhpp Lys^(D)Pro^(L)Pro 95 950.8 1.92 NO: 4 5. SEQ ID Hhpp His Ala Cys Ser Ala^(D)Pro Dab Arg Tyr Cys Tyr Gln Lys ^(D)Pro^(L)Pro 85 933.4 1.69 NO: 56. SEQ ID Tyr Ahb Ala Cys Ser Ala ^(D)Pro Dab Arg Tyr Cys Tyr Gln Lys^(D)Pro^(L)Pro 95 914.4 1.65 NO: 6 7. SEQ ID Tyr His Ala Cys ^(D)Ser Lac^(D)Pro Dab Arg Tyr Cys Tyr Gln Lys ^(D)Pro^(L)Pro 95 933.6 1.75 NO: 78. SEQ ID Tyr His Ala Cys Arg Ala ^(D)Pro Dab Arg Tyr Cys Tyr Gln Ahb^(D)Pro^(L)Pro 95 954.3 1.54 NO: 8 9. SEQ ID Tyr His Lac Cys Arg Ala^(D)Pro Dab Arg Tyr Cys Tyr Gln Lys ^(D)Pro^(L)Pro 95 968.4 1.60 NO: 910. SEQ ID Tyr His Ala Cys Arg Ala ^(D)Pro Dab Arg Tyr Cys Tyr ^(D)GlnAhb ^(D)Pro^(L)Pro 95 954.6 1.50 NO: 10 Cys in pos. 4 and 11 in Ex. 1-11form a disulfide bridge, ^(a))%-purity of compounds after prep. HPLC.

2. Biological Methods

2.1. Preparation of the Depsipeptides

Lyophilized depsipeptides were weighed on a Microbalance (Mettler MT5)and dissolved in sterile water to a final concentration of 1 mM ordissolved in DMSO to a final concentration of 10 mM. Stock solutionswere kept at +4° C., light protected. In case of DMSO stock solutionsthe biological assays were carried out under assay conditions havingless than 1% DMSO.

2.2. Cell Culture

Mouse pre-B cells were cultured in RPMI1640 plus 5% FBS,antibiotic/antimycotic, non essential amino acid, 50 μMβ-mercaptoethanol and 1 mM natrium pyruvate. HELA cells were maintainedin RPMI1640 plus 10% FBS, pen/strept and 2 mM L-glutamine. Cos-7 cellswere grown in DMEM medium with 4500 mg/mL glucose supplemented with 10%FCS, pen/strept and 2 mM L-glutamine. All cell lines were grown at 37°C. at 5% CO₂. Cell media, media supplements, PBS-buffer, HEPES,antibiotic/antimycotic, pen/strept, non essential amino acid,L-glutamine, β-mercaptoethanol and sera were purchased from Gibco(Pailsey, UK). All fine chemicals were supplied by Merck (Darmstadt,Germany).

2.3. Ca²⁺-Assay: CXCR4-Antagonizing Activity of the Depsipeptides

Increases in intracellular calcium were monitored using a Flexstation384 (Molecular Devices, Sunnyvale, Calif.) to assay the depsipeptidesfor CXCR4 antagonism in a mouse pre-B cell line 300-19 stablytransfected with human CXCR4 (E. Oberlin, A. Amara, F. Bachelerie, C.Bessia, J.-L. Virelizier, F. Arenzana-Seisdedos, O. Schwartz, J.-M.Heard, I. Clark-Lewis, D. F. Legler, M. Loetscher, M. Baggiolini, B.Moser, Nature 1996, 382, 833-835; M. Loetscher, T. Geiser, T. O'Reilly,R. Zwalen, M. Baggiolini, B. Moser, J. Biol. Chem. 1994, 269, 232-237;M. D'Apuuo, A. Rolink, M. Loetscher, J. A. Hoxie, I. Clark-Lewis, F.Melchors, M. Baggiolini, B. Moser, Eur. J. Immunol. 1997, 27,1788-1793). The cells were batch loaded with the Calcium 4 Assay kit(Molecular Devices) in assay buffer (Hanks Balanced salt solution[HBSS], 20 mM HEPES, pH 7.4, 0.1% BSA) for 1 h at room temperature andlabeled cells were dispensed into black well assays plates (Costar No.3603). Calcium mobilization induced by stromal-derived factor-1 (SDF-1)was measured in the Flexstation 384 (excitation: 485 nm; emission: 525nm) for 90 seconds. Antagonist activity of depsipeptides was determinedby spiking the cells with compounds prior to SDF-1 addition. Doseresponse curves (compound concentration versus % maximum response forSDF-1) were determined for each antagonist and IC₅₀ values werecalculated by fitting the data to a four parameter logistic equationusing SoftmaxPro 4.8 (Molecular Devices).

2.4. Cytotoxicity Assay

The cytotoxicity of the depsipeptides to HELA cells (Acc57) and COS-7cells (CRL-1651) was determined using the MTT reduction assay (T.Mossman, J. Immunol. Meth. 1983, 65, 55-63; M. V. Berridge, A. S. Tan,Arch. Biochem. Biophys. 1993, 303, 474-482). Briefly, the method was asfollows: 7000 HELA cells/well and 4500 COS-7 cells/well were seeded andgrown in 96-well microtiter plates for 24 h at 37° C. at 5% CO₂.Thereafter, time zero (Tz) was determined by MTT reduction (see below).The supernatant of the remaining wells was discarded, and fresh mediumand compounds in serial dilutions (12.5, 25 and 50 μM, triplicates) werepipetted into the wells. After incubation of the cells for 48 h at 37°C. at 5% CO₂ the supernatant was discarded again and 100 μL MTT reagent(0.5 mg/mL in RPMI1640 and DMEM, respectively)/well was added. Followingincubation at 37° C. for 2 h the media were aspirated and the cells werespiked (100 μL isopropanol/well). The absorbance of the solubilizedformazan was measured at 595 nm (OD₅₉₅peptide). For each concentrationaverages were calculated from triplicates. The percentage of growth wascalculated as follows: (OD₅₉₅peptide-OD₅₉₅Tz-OD₅₉₅Emptywell)/(OD₅₉₅Tz-OD₅₉₅Empty well)×100%. The GI₅₀ (Growth Inhibition)concentrations were calculated for each depsipeptide by using a trendline function for the concentrations (50, 25, 12.5 and 0 μM), thecorresponding percentages and the value 50, (=TREND (C₅₀:C₀, %₅₀:%₀,50).

2.5. Hemolysis

The depsipeptides were tested for their hemolytic activity against humanred blood cells (hRBC). Fresh hRBC were washed three times withphosphate buffered saline (PBS) and centrifuged for 10 min at 2000×g.Compounds (100 μM) were incubated with 20% hRBC (v/v) for 1 h at 37° C.The final erythrocyte concentration was approximately 0.9×10⁹ cells/mL.A value of 0% and 100% cell lyses, respectively, was determined byincubation of hRBC in the presence of PBS alone and 0.1% Triton X-100 inH₂O, respectively. The samples were centrifuged, the supernatants were20-fold diluted in PBS buffer and the optical densities (OD) weremeasured at 540 nm. The 100% lyses value (OD₅₄₀H₂O) gave an OD₅₄₀ ofapproximately 1.3-1.8.

Percent hemolysis was calculated as follows:(OD₅₄₀peptide/OD₅₄₀H₂O)×100%.

2.6. Plasma Stability

The stability of the depsipeptides in human and mouse plasma wasdetermined by applying the following method: 315 μL/deep well of freshlythawed human plasma (Basler Blutspende-dienst) and mouse plasma (HarlanSera-Lab, UK), respectively, were spiked with 35 μL/well of compound inPBS (100 μM, triplicate) and incubated at 37° C. At t=0, 15, 30, 60, 120and 240 min aliquots of 50 μL were transferred to filtration plate wellscontaining 150 μL/well of acetonitrile. Following shaking for 2 min theoccurred suspensions were filtrated by vacuum and finally, 100 μL ofeach filtrate were transferred to a propylene microtiter plate, andanalyzed by LC/MS as follows: Column: Waters, XBridge C18, mobilephases: (A) water+0.1% formic acid and (B) acetonitrile/water, 95/5(v/v)+0.1% formic acid, gradient: 5%-100% (B) in 2 minutes, electrosprayionization, MRM detection (triple quadrupole). The peak areas weredetermined and triplicate values are averaged. The stability isexpressed in percent of the initial value at t=0. (t_(x)/t₀×100). Byusing the TREND function of EXCEL (Microsoft Office 2003) T_(1/2) weredetermined.

TABLE 1 Ex. IC50% [nM] ± SD, CXCR4 receptor 1 0.8 ± 0.5 2 0.7 ± 0.7 32.7 ± 1.4 4 4.4 ± 1.6 5 3.3 ± 1.1 6 13.5 ± 5   7 2.1 ± 0.5 8 82.4 ± 12.89 20.8 ± 8.3  10 16.6 ± 1.5 

TABLE 2 Cytotoxicity Hela Cos-7 Cells Cells Hemolysis PlasmastabilityGI₅₀ GI₅₀ at 100 μM human pl. mouse pl. Ex. [μM] [μM] [%] T_(1/2) [min]T_(1/2) [min] 1 2 12 0.2 79 73 2 >50 >50 0.7 240 240 3 >50 >50 0.4 81136 4 >50 >50 1.0 240 240 5 >50 >50 1.5 240 240 6 >50 >50 1.0 4.2 4.37 >50 >50 0.2 62 51 8 >50 >50 0.4 0 0 9 >50 >50 0.4 85 74 10 >50 >50 0.35.1 5.3

1. Compounds of the general formulae

wherein

are groups of one of the formulae

wherein

is Gly or Glycolic acid residue, or the residue of an L-α-amino acidwith B being a residue of formula —NR²⁰CH(R⁷¹)—, or —NR²⁰CH(R⁷²)—, or—NR²⁰CH(R⁷³)— or —NR²⁰CH(R⁷⁴)— or —NR²⁰CH(R⁸⁴)— or the residue of anL-α-hydroxy acid with B being a residue of formula —OCH(R⁷¹)— or—OCH(R⁷²)— or —OCH(R⁷³)— or —OCH(R⁷⁴)— or —OCH(R⁸⁴)—, or the enantiomerof one of the groups A1 to A69 and A105, or the enantiomer of the groupsA106 to A110 as defined hereinafter;

is a group of one of the formulae

R¹ is H; lower alkyl; or aryl-lower alkyl; R² is H; alkyl; alkenyl;—(CH₂)_(m)(CHR⁶¹)_(s)OR⁵⁵; —(CH₂)_(m)(CHR⁶¹)_(s)SR⁵⁶;—(CH₂)_(m)(CHR⁶¹)_(s)NR³³R³⁴; —(CH₂)_(m)(CHR⁶¹)_(s)OCONR³³R⁷⁵;—(CH₂)_(m)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷;—(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂;—(CH₂)_(o)(CHR⁶¹)_(s)SO₂R⁶²; or —(CH₂)_(o)(CHR⁶¹)_(s)R⁷⁷; R³ is H;alkyl; alkenyl; —(CH₂)_(m)(CHR⁶¹)_(s)OR⁵⁵; —(CH₂)_(m)(CHR⁶¹)_(s)SR⁵⁶;—(CH₂)_(m)(CHR⁶¹)_(s)NR³³R³⁴; —(CH₂)_(m)(CHR⁶¹)_(s)OCONR³³R⁷⁵;—(CH₂)_(m)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷;—(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂;—(CH₂)_(o)(CHR⁶¹)_(s)SO₂R⁶²; or —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸; R⁴ is H;alkyl; alkenyl; —(CH₂)_(m)(CHR⁶¹)_(s)OR⁵⁵; —(CH₂)_(m)(CHR⁶¹)_(s)SR⁵⁶;—(CH₂)_(m)(CHR⁶¹)_(s)NR³³R³⁴; —(CH₂)_(m)(CHR⁶¹)_(s)OCONR³³R⁷⁵;—(CH₂)_(m)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(p)(CHR⁶¹)_(s)COOR⁵⁷;—(CH₂)_(p)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; —(CH₂)_(p)(CHR⁶¹)_(s)PO(OR⁶⁰)₂—;—(CH₂)_(p)(CHR⁶¹)_(s)SO₂R⁶²; or —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸; R⁵ isalkyl; alkenyl; —(CH₂)_(o)(CHR⁶¹)_(s)OR⁵⁵; —(CH₂)_(o)(CHR⁶¹)_(s)SR⁵⁶;—(CH₂)_(o)(CHR⁶¹)_(s)NR³³R³⁴; —(CH₂)_(o)(CHR⁶¹)_(s)OCONR³³R⁷⁵;—(CH₂)_(o)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷;—(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂—;—(CH₂)_(o)(CHR⁶¹)_(s)SO₂R⁶²; or —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸; R⁶ is H;alkyl; alkenyl; —(CH₂)_(o)(CHR⁶¹)_(s)OR⁵⁵; —(CH₂)_(o)(CHR⁶¹)_(s)SR⁵⁶;—(CH₂)_(o)(CHR⁶¹)_(s)NR³³R³⁴; —(CH₂)_(o)(CHR⁶¹)_(s)OCONR³³R⁷⁵;—(CH₂)_(o)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷;—(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂;—(CH₂)_(o)(CHR⁶¹)_(s)SO₂R⁶²; or —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸; R⁷ isalkyl; alkenyl; —(CH₂)_(q)(CHR⁶¹)_(s)OR⁵⁵; —(CH₂)_(q)(CHR⁶¹)_(s)NR³³R³⁴;—(CH₂)_(q)(CHR⁶¹)_(s)OCONR³³R⁷⁵; —(CH₂)_(q)(CHR⁶¹)_(s)NR²⁰CONR³³R⁶²;—(CH₂)_(r)(CHR⁶¹)_(s)COOR⁵⁷; —(CH₂)_(r)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹;—(CH₂)_(r)(CHR⁶¹)_(s)PO(OR⁶⁰)₂; —(CH₂)_(r)(CHR⁶¹)_(s)SO₂R⁸²; or—(CH₂)_(r)(CHR⁶¹)_(s)C₆H₄R⁸; R⁸ is H; Cl; F; CF₃; NO₂; lower alkyl;lower alkenyl; aryl; aryl-lower alkyl;—(CH₂)_(o)(CHR⁶¹)_(s)R⁷⁷—(CH₂)_(o)(CHR⁶¹)_(s)OR⁵⁵;—(CH₂)_(o)(CHR⁶¹)_(s)SR⁵⁶; —(CH₂)_(o)(CHR⁶¹)NR³³R³⁴;—(CH₂)_(o)(CHR⁶¹)_(s)OCONR³³R⁷⁵; —(CH₂)_(o)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²;—(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷; —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹;—(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂; —(CH₂)_(o)(CHR⁶¹)_(s)SO₂R⁶²; or—(CH₂)_(o)(CHR⁶¹)_(s)COR⁶⁴; R⁹ is alkyl; alkenyl;—(CH₂)_(o)(CHR⁶¹)_(s)OR⁵⁵; —(CH₂)_(o)(CHR⁶¹)_(s)SR⁵⁶;—(CH₂)_(o)(CHR⁶¹)_(s)NR³³R³⁴; —(CH₂)_(o)(CHR⁶¹)_(s)OCONR³³R⁷⁵;—(CH₂)_(o)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷;—(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂;—(CH₂)_(o)(CHR⁶¹)_(s)SO₂R⁶²; or —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸; R¹⁰ isalkyl; alkenyl; —(CH₂)_(o)(CHR⁶¹)_(s)OR⁵⁵; —(CH₂)_(o)(CHR⁶¹)_(s)SR⁵⁶;—(CH₂)_(o)(CHR⁶¹)_(s)NR³³R³⁴; —(CH₂)_(o)(CHR⁶¹)_(s)OCONR³³R⁷⁵;—(CH₂)_(o)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷;—(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂;—(CH₂)_(o)(CHR⁶¹)_(s)SO₂R⁶²; or —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸; R¹¹ is H;alkyl; alkenyl; —(CH₂)_(m)(CHR⁶¹)_(s)OR⁵⁵; —(CH₂)_(m)(CHR⁶¹)_(s)NR³³R³⁴;—(CH₂)_(m)(CHR⁶¹)_(s)OCONR³³R⁷⁵; —(CH₂)_(m)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²;—(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷; —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹;—(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂; —(CH₂)_(o)(CHR⁶¹)_(s)SO₂R⁶²; or—(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸; R¹² is H; alkyl; alkenyl;—(CH₂)_(m)(CHR⁶¹)_(s)OR⁵⁵; —(CH₂)_(m)(CHR⁶¹)_(s)SR⁵⁶;—(CH₂)_(m)(CHR⁶¹)_(s)NR³³R³⁴; —(CH₂)_(m)(CHR⁶¹)_(s)OCONR³³R⁷⁵;—(CH₂)_(m)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(r)(CHR⁶¹)_(s)COOR⁵⁷;—(CH₂)_(r)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; —(CH₂)_(r)(CHR⁶¹)_(s)PO(OR⁶⁰)₂;—(CH₂)_(r)(CHR⁶¹)_(s)SO₂R⁶²; or —(CH₂)_(r)(CHR⁶¹)_(s)C₆H₄R⁸; R¹³ isalkyl; alkenyl; —(CH₂)_(q)(CHR⁶¹)_(s)OR⁵⁵; —(CH₂)_(q)(CHR⁶¹)_(s)SR⁵⁶;—(CH₂)_(q)(CHR⁶¹)_(s)NR³³R³⁴; —(CH₂)_(q)(CHR⁶¹)_(s)OCONR³³R⁷⁵;—(CH₂)_(q)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(q)(CHR⁶¹)_(s)COOR⁵⁷;—(CH₂)_(q)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; —(CH₂)_(q)(CHR⁶¹)_(s)PO(OR⁶⁰)₂;—(CH₂)_(q)(CHR⁶¹)_(s)SO₂R⁶²; or —(CH₂)_(q)(CHR⁶¹)_(s)C₆H₄R⁸; R¹⁴ is H;alkyl; alkenyl; —(CH₂)_(m)(CHR⁶¹)_(s)OR⁵⁵; —(CH₂)_(m)(CHR⁶¹)_(s)NR³³R³⁴;—(CH₂)_(m)(CHR⁶¹)_(s)OCONR³³R⁷⁵; —(CH₂)_(m)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²;—(CH₂)_(q)(CHR⁶¹)_(s)COOR⁵⁷; —(CH₂)_(q)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹;—(CH₂)_(q)(CHR⁶¹)_(s)PO(OR⁶⁰)₂; —(CH₂)_(q)(CHR⁶¹)_(s)SOR⁶²; or—(CH₂)_(q)(CHR⁶¹)_(s)C₆H₄R⁸; R¹⁵ is alkyl; alkenyl;—(CH₂)_(o)(CHR⁶¹)_(s)OR⁵⁵; —(CH₂)_(o)(CHR⁶¹)_(s)SR⁵⁶;—(CH₂)_(o)(CHR⁶¹)_(s)NR³³R³⁴; —(CH₂)_(o)(CHR⁶¹)_(s)OCONR³³R⁷⁵;—(CH₂)_(o)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷;—(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂;—(CH₂)_(o)(CHR⁶¹)_(s)SO₂R⁶²; or —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸; R¹⁶ isalkyl; alkenyl; —(CH₂)_(o)(CHR⁶¹)_(s)OR⁵⁵; —(CH₂)_(o)(CHR⁶¹)_(s)SR⁵⁶;—(CH₂)_(o)(CHR⁶¹)_(s)NR³³R³⁴; —(CH₂)_(o)(CHR⁶¹)_(s)OCONR³³R⁷⁵;—(CH₂)_(o)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷;—(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂;—(CH₂)_(o)(CHR⁶¹)_(s)SO₂R⁶²; or —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸; R¹⁷ isalkyl; alkenyl; —(CH₂)_(q)(CHR⁶¹)_(s)OR⁵⁵; —(CH₂)_(q)(CHR⁶¹)_(s)SR⁵⁶;—(CH₂)_(q)(CHR⁶¹)_(s)NR³³R³⁴; —(CH₂)_(q)(CHR⁶¹)_(s)OCONR³³R⁷⁵;—(CH₂)_(q)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(q)(CHR⁶¹)_(s)COOR⁵⁷;—(CH₂)_(q)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; —(CH₂)_(q)(CHR⁶¹)_(s)PO(OR⁶⁰)₂;—(CH₂)_(q)(CHR⁶¹)_(s)SO₂R⁶²; or —(CH₂)_(q)(CHR⁶¹)_(s)C₆H₄R⁸; R¹⁸ isalkyl; alkenyl; —(CH₂)_(p)(CHR⁶¹)_(s)OR⁵⁵; —(CH₂)_(p)(CHR⁶¹)_(s)SR⁵⁶;—(CH₂)_(p)(CHR⁶¹)_(s)NR³³R³⁴; —(CH₂)_(p)(CHR⁶¹)_(s)OCONR³³R⁷⁵;—(CH₂)_(p)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(p)(CHR⁶¹)_(s)COOR⁵⁷;—(CH₂)_(p)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; —(CH₂)_(p)(CHR⁶¹)_(s)PO(OR⁶⁰)₂;—(CH₂)_(p)(CHR⁶¹)_(s)SO₂R⁶²; or —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸; R¹⁹ islower alkyl; —(CH₂)_(p)(CHR⁶¹)_(s)OR⁵⁵; —(CH₂)_(p)(CHR⁶¹)_(s)SR⁵⁶;—(CH₂)_(p)(CHR⁶¹)_(s)NR³³R³⁴; —(CH₂)_(p)(CHR⁶¹)_(s)OCONR³³R⁷⁵;—(CH₂)_(p)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(p)(CHR⁶¹)_(s)COOR⁵⁷;—(CH₂)_(p)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; —(CH₂)_(p)(CHR⁶¹)_(s)PO(OR⁶⁰)₂;—(CH₂)_(p)(CHR⁶¹)_(s)SO₂R⁶²; or —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸; or R¹⁸ andR¹⁹ taken together can form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;—(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; R²⁰ is H; alkyl; alkenyl; oraryl-lower alkyl; R²¹ is H; alkyl; alkenyl; —(CH₂)_(o)(CHR⁶¹)_(s)OR⁵⁵;—(CH₂)_(o)(CHR⁶¹)_(s)SR⁵⁶; —(CH₂)_(o)(CHR⁶¹)_(s)NR³³R³⁴;—(CH₂)_(o)(CHR⁶¹)_(s)OCONR³³R⁷⁵; —(CH₂)_(o)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²;—(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷; —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹;—(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂; —(CH₂)_(o)(CHR⁶¹)_(s)SO₂R⁶²; or—(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸; R²² is H; alkyl; alkenyl;—(CH₂)_(o)(CHR⁶¹)_(s)OR⁵⁵; —(CH₂)_(o)(CHR⁶¹)_(s)SR⁵⁶;—(CH₂)_(o)(CHR⁶¹)_(s)NR³³R³⁴; —(CH₂)_(o)(CHR⁶¹)_(s)OCONR³³R⁷⁵;—(CH₂)_(o)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷;—(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂;—(CH₂)_(o)(CHR⁶¹)_(s)SO₂R⁶²; or —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸; R²³ isalkyl; alkenyl; —(CH₂)_(o)(CHR⁶¹)_(s)OR⁵⁵; —(CH₂)_(o)(CHR⁶¹)_(s)SR⁵⁶;—(CH₂)_(o)(CHR⁶¹)_(s)NR³³R³⁴; —(CH₂)_(o)(CHR⁶¹)_(s)OCONR³³R⁷⁵;—(CH₂)_(o)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷;—(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂;—(CH₂)_(o)(CHR⁶¹)_(s)SO₂R⁶²; or —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸; R²⁴ isalkyl; alkenyl; —(CH₂)_(o)(CHR⁶¹)_(s)OR⁵⁵; —(CH₂)_(o)(CHR⁶¹)_(s)SR⁵⁶;—(CH₂)_(o)(CHR⁶¹)_(s)NR³³R³⁴; —(CH₂)_(o)(CHR⁶¹)_(s)OCONR³³R⁷⁵;—(CH₂)_(o)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷;—(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂;—(CH₂)_(o)(CHR⁶¹)_(s)SO₂R⁶²; or —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸; R²⁵ is H;alkyl; alkenyl; —(CH₂)_(m)(CHR⁶¹)_(s)OR⁵⁵; —(CH₂)_(m)(CHR⁶¹)_(s)SR⁵⁶;—(CH₂)_(m)(CHR⁶¹)_(o)NR³³R³⁴; —(CH₂)_(m)(CHR⁶¹)_(s)OCONR³³R⁷⁵;—(CH₂)_(m)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷;—(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂;—(CH₂)_(o)(CHR⁶¹)_(s)SO₂R⁶²; or —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸; R²⁶ is H;alkyl; alkenyl; —(CH₂)_(m)(CHR⁶¹)_(s)OR⁵⁵; —(CH₂)_(m)(CHR⁶¹)_(s)SR⁵⁶;—(CH₂)_(m)(CHR⁶¹)_(s)NR³³R³⁴; —(CH₂)_(m)(CHR⁶¹)_(s)OCONR³³R⁷⁵;—(CH₂)_(m)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷;—(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂;—(CH₂)_(o)(CHR⁶¹)_(s)SO₂R⁶²; or —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸; or R²⁵ andR²⁶ taken together can form: —(CH₂)₂₋₆—; —(CH₂)_(r)O(CH₂)_(r);—(CH₂)_(r)S(CH₂)_(r)—; or —(CH₂)_(r)NR⁵⁷(CH₂)_(r)—; R²⁷ is H; alkyl;alkenyl; —(CH₂)_(o)(CHR⁶¹)_(s)OR⁵⁵; —(CH₂)_(o)(CHR⁶¹)_(s)SR⁵⁶;—(CH₂)_(o)(CHR⁶¹)_(s)NR³³R³⁴; —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷;—(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; —(CH₂)_(o)(CHR⁶¹)_(s)OCONR³³R⁷⁵;—(CH₂)_(o)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂;—(CH₂)_(o)(CHR⁶¹)_(s)SO₂R⁶²; or —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸; R²⁸ isalkyl; alkenyl; —(CH₂)_(o)(CHR⁶¹)_(s)—OR⁵⁵; —(CH₂)_(o)(CHR⁶¹)_(s)SR⁵⁶;—(CH₂)_(o)(CHR⁶¹)_(s)NR³³R³⁴; —(CH₂)_(o)(CHR⁶¹)_(s)OCONR³³R⁷⁵;—(CH₂)_(o)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷;—(CH₂)_(o)(CHR⁶¹)^(s)CONR⁵⁸R⁵⁹; —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂;—(CH₂)_(o)(CHR⁶¹)_(s) SO₂R⁶²; or —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸; R²⁹ isalkyl; alkenyl; —(CH₂)_(o)(CHR⁶¹)_(s)OR⁵⁵; —(CH₂)_(o)(CHR⁶¹)_(s)SR⁵⁶;—(CH₂)_(o)(CHR⁶¹)_(s)NR³³R³⁴; —(CH₂)_(o)(CHR⁶¹)_(s)OCONR³³R⁷⁵;—(CH₂)_(o)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷;—(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂;—(CH₂)_(o)(CHR⁶¹)_(s)SO₂R⁶²; or —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸; R³⁰ is H;alkyl; alkenyl; or aryl-lower alkyl; R³¹ is H; alkyl; alkenyl;—(CH₂)_(p)(CHR⁶¹)_(s)OR⁵⁵; —(CH₂)_(p)(CHR⁶¹)_(s)NR³³R³⁴;—(CH₂)_(p)(CHR⁶¹)_(s)OCONR³³R⁷⁵; —(CH₂)_(p)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²;—(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷; —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹;—(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂; —(CH₂)_(o)(CHR⁶¹)_(s)SO₂R⁶²; or—(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸; R³² is H; lower alkyl; or aryl-lower alkyl;R³³ is H; alkyl, alkenyl; —(CH₂)_(m)(CHR⁶¹)_(s)OR⁵⁵;—(CH₂)_(m)(CHR⁶¹)_(s)NR³⁴R⁶³; —(CH₂)_(m)(CHR⁶¹)_(s)OCONR⁷⁵R⁸²;—(CH₂)_(m)(CHR⁶¹)_(s)NR²⁰CONR⁷⁸R⁸²; —(CH₂)_(o)(CHR⁶¹)_(s)COR⁶⁴;—(CH₂)_(o)(CHR⁶¹)_(s)—CONR⁵⁸R⁵⁹, —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂;—(CH₂)_(o)(CHR⁶¹)_(s)SO₂R⁶²; or —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸; R³⁴ is H;lower alkyl; aryl, or aryl-lower alkyl; or R³³ and R³⁴ taken togethercan form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; R³⁵ is H; alkyl; alkenyl; —(CH₂)_(m)(CHR⁶¹)_(s)OR⁵⁵;—(CH₂)_(m)(CHR⁶¹)_(s)NR³³R³⁴; —(CH₂)_(m)(CHR⁶¹)_(s)OCONR³³R⁷⁵;—(CH₂)_(m)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(p)(CHR⁶¹)_(s)COOR⁵⁷;—(CH₂)_(p)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; —(CH₂)_(p)(CHR⁶¹)_(s)PO(OR⁶⁰)₂;—(CH₂)_(p)(CHR⁶¹)_(s)SO₂R⁶²; or —(CH₂)_(p)(CHR⁶¹)_(s)C₆H₄R⁸; R³⁶ is H,alkyl; al kenyl; —(CH₂)_(o)(CHR⁶¹)_(s)OR⁵⁵;—(CH₂)_(p)(CHR⁶¹)_(s)NR³³R³⁴; —(CH₂)_(p)(CHR⁶¹)_(s)OCONR³³R⁷⁵;—(CH₂)_(p)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(p)(CHR⁶¹)_(s)COOR⁵⁷;—(CH₂)_(p)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; —(CH₂)_(p)(CHR⁶¹)_(s)PO(OR⁶⁰)₂;—(CH₂)_(p)(CHR⁶¹)_(s)SO₂R⁶²; or —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸; R³⁷ is H;F; Br; Cl; NO₂; CF₃; lower alkyl; —(CH₂)_(p)(CHR⁶¹)_(s)OR⁵⁵;—(CH₂)_(p)(CHR⁶¹)_(s)NR³³R³⁴; —(CH₂)_(p)(CHR⁶¹)_(s)OCONR³³R⁷⁵;—(CH₂)_(p)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(o)(CHR⁶¹)_(s)COOR₅₇;—(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹: —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂;—(CH₂)_(o)(CHR⁶¹)_(s)SO₂R⁶²; or —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸; R³⁸ is H;F; Br; Cl; NO₂; CF₃; alkyl; alkenyl; —(CH₂)_(p)(CHR⁶¹)_(s)OR⁵⁵;—(CH₂)_(p)(CHR⁶¹)_(s)NR³³R³⁴; —(CH₂)_(p)(CHR⁶¹)_(s)OCONR³³R⁷⁵;—(CH₂)_(p)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷;—(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂;—(CH₂)_(o)(CHR⁶¹)_(s)SO₂R⁶²; or —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸; R³⁹ is H;alkyl; alkenyl; or aryl-lower alkyl; R⁴⁰ is H; alkyl; alkenyl; oraryl-lower alkyl; R⁴¹ is H; F; Br; Cl; NO₂; CF₃; alkyl; alkenyl;—(CH₂)_(p)(CHR⁶¹)_(s)OR⁵⁵; —(CH₂)_(p)(CHR⁶¹)_(s)NR³³R³⁴;—(CH₂)_(p)(CHR⁶¹)_(s)OCONR³³R⁷⁵; —(CH₂)_(p)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²;—(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷; —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹;—(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂; —(CH₂)_(o)(CHR⁶¹)_(s)SO₂R⁶²; or—(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸; R⁴² is H; F; Br; Cl; NO₂; CF₃; alkyl;alkenyl; —(CH₂)_(p)(CHR⁶¹)_(s)OR⁵⁵; —(CH₂)_(p)(CHR⁶¹)_(s)NR³³R³⁴;—(CH₂)_(p)(CHR⁶¹)_(s)OCONR³³R⁷⁵; —(CH₂)_(p)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²;—(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷; —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹;—(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂; —(CH₂)_(o)(CHR⁶¹)_(s)SO₂R⁶²; or—(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸; R⁴³ is H; alkyl; alkenyl;—(CH₂)_(m)(CHR⁶¹)_(s)OR⁵⁵; —(CH₂)_(m)(CHR⁶¹)_(s)NR³³R³⁴;—(CH₂)_(m)(CHR⁶¹)_(s)OCONR³³R⁷⁵; —(CH₂)_(m)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²;—(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷; —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹;—(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂; —(CH₂)_(o)(CHR⁶¹)_(s)SO₂R⁶²; or—(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸; R⁴⁴ is alkyl; alkenyl;—(CH₂)_(r)(CHR⁶¹)_(s)OR⁵⁵; —(CH₂)_(r)(CHR⁶¹)_(s)SR⁵⁶;—(CH₂)_(r)(CHR⁶¹)_(s)NR³³R³⁴; —(CH₂)_(r)(CHR⁶¹)_(s)OCONR³³R⁷⁵;—(CH₂)_(r)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(r)(CHR⁶¹)_(s)COOR⁵⁷;—(CH₂)_(r)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; —(CH₂)_(r)(CHR⁶¹)_(s)PO(OR⁶⁰)₂;—(CH₂)_(r)(CHR⁶¹)_(s)SO₂R⁶²; or —(CH₂)_(r)(CHR⁶¹)_(s)C₆H₄R⁸; R⁴⁵ is H;alkyl; alkenyl; —(CH₂)_(o)(CHR⁶¹)_(s)OR⁵⁵; —(CH₂)_(o)(CHR⁶¹)_(s)SR⁵⁶;—(CH₂)_(o)(CHR⁶¹)_(s)NR³³R³⁴; —(CH₂)_(o)(CHR⁶¹)_(s)OCONR³³R⁷⁵;—(CH₂)_(o)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷;—(CH₂)_(s)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; —(CH₂)_(s)(CHR⁶¹)_(s)PO(OR⁶⁰)₂;—(CH₂)_(s)(CHR⁶¹)_(s)SO₂R⁶²; or —(CH₂)_(s)(CHR⁶¹)_(s)C₆H₄R⁸; R⁴⁶ is H;alkyl; alkenyl; or —(CH₂)_(o)(CHR⁶¹)_(p)C₆H₄R⁸; R⁴⁷ is H; alkyl;alkenyl; or —(CH₂)_(o)(CHR⁶¹)_(s)OR⁵⁵; R⁴⁸ is H; lower alkyl; loweralkenyl; or aryl-lower alkyl; R⁴⁹ is H; alkyl; alkenyl;—(CHR⁶¹)_(s)COOR⁵⁷; (CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; —(CHR⁶¹)_(s)PO(OR⁶⁰)₂;—(CHR⁶¹)_(s)SOR⁶²; or —(CHR⁶¹)_(s)C₆H₄R⁸; R⁵⁰ is H; lower alkyl; oraryl-lower alkyl; R⁵¹ is H; alkyl; alkenyl; —(CH₂)_(m)(CHR⁶¹)_(s)OR⁵⁵;—(CH₂)_(m)(CHR⁶¹)_(s)SR⁵⁶; —(CH₂)_(m)(CHR⁶¹)_(s)NR³³R³⁴;—(CH₂)_(m)(CHR⁶¹)_(s)OCONR³³R⁷⁵; —(CH₂)_(m)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²;—(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷; —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹;—(CH₂)_(o)(CHR⁶¹)_(p)PO(OR⁶⁰)₂; —(CH₂)_(p)(CHR⁶¹)_(s)SO₂R⁶²; or—(CH₂)_(p)(CHR⁶¹)_(s)C₆H₄R⁸; R⁵² is H; alkyl; alkenyl;—(CH₂)_(m)(CHR⁶¹)_(s)OR⁵⁵; —(CH₂)_(m)(CHR⁶¹)_(s)SR⁵⁶;—(CH₂)_(m)(CHR⁶¹)_(s)NR³³R³⁴; —(CH₂)_(m)(CHR⁶¹)_(s)OCONR³³R⁷⁵;—(CH₂)_(m)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷;—(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; —(CH₂)_(o)(CHR⁶¹)_(p)PO(OR⁶⁰)₂;—(CH₂)_(p)(CHR⁶¹)_(s)SO₂R⁶²; or —(CH₂)_(p)(CHR⁶¹)_(s)C₆H₄R⁸; R⁵³ is H;alkyl; alkenyl; —(CH₂)_(m)(CHR⁶¹)_(s)OR⁵⁵; —(CH₂)_(m)(CHR⁶¹)_(s)SR⁵⁶;—(CH₂)_(m)(CHR⁶¹)_(s)NR³³R³⁴; —(CH₂)_(m)(CHR⁶¹)_(s)OCONR³³R⁷⁵;—(CH₂)_(m)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷;—(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; —(CH₂)_(o)(CHR⁶¹)_(p)PO(OR⁶⁰)₂;—(CH₂)_(p)(CHR⁶¹)_(s)SO₂R⁶²; or —(CH₂)_(p)(CHR⁶¹)_(s)C₆H₄R⁸; R⁵⁴ is H;alkyl; alkenyl; —(CH₂)_(m)(CHR⁶¹)_(s)OR⁵⁵; —(CH₂)_(m)(CHR⁶¹)_(s)NR³³R³⁴;—(CH₂)_(m)(CHR⁶¹)_(s)OCONR³³R⁷⁵; —(CH₂)_(m)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²;—(CH₂)_(o)(CHR⁶¹)COOR⁵⁷; —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; or—(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸; R⁵⁵ is H; lower alkyl; lower alkenyl;aryl-lower alkyl; —(CH₂)_(m)(CHR⁶¹)_(s)OR⁵⁷;—(CH₂)_(m)(CHR⁶¹)_(s)NR³⁴R⁶³; —(CH₂)_(m)(CHR⁶¹)_(s)OCONR⁷⁵R⁸²;—(CH₂)_(m)(CHR⁶¹)_(s)NR²⁰CONR⁷⁸R⁸²; —(CH₂)_(o)(CHR⁶¹)_(s)—COR⁶⁴;—(CH₂)_(o)(CHR⁶¹)COOR⁵⁷; or —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; R⁵⁶ is H;lower alkyl; lower alkenyl; aryl-lower alkyl; —(CH₂)_(m)(CHR⁶¹)_(s)OR⁵⁷;—(CH₂)_(m)(CHR⁶¹)_(s)NR³⁴R⁶³; —(CH₂)_(m)(CHR⁶¹)_(s)OCONR⁷⁵R⁸²;—(CH₂)_(m)(CHR⁶¹)_(s)NR²⁰CONR⁷⁸R⁸²; —(CH₂)_(o)(CHR⁶¹)_(s)—COR⁶⁴; or—(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; R⁵⁷ is H; lower alkyl; lower alkenyl;aryl lower alkyl; or heteroaryl lower alkyl; R⁵⁸ is H; lower alkyl;lower alkenyl; aryl; heteroaryl; aryl-lower alkyl; or heteroaryl-loweralkyl; R⁵⁹ is H; lower alkyl; lower alkenyl; aryl; heteroaryl;aryl-lower alkyl; or heteroaryl-lower alkyl; or R⁵⁸ and R⁵⁹ takentogether can form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; R⁶⁰ is H; lower alkyl; lower alkenyl; aryl; oraryl-lower alkyl; R⁶¹ is alkyl; alkenyl; aryl; heteroaryl; aryl-loweralkyl; heteroaryl-lower alkyl; —(CH₂)_(p)OR⁵⁵; —(CH₂)_(p)NR³³R³⁴;—(CH₂)_(p)OCONR⁷⁵R⁸²; —(CH₂)_(p)NR²⁰CONR⁷⁸R⁸²; —(CH₂)_(o)COOR³⁷;—(CH₂)_(o)PO(OR⁶⁰)₂; R⁶² is lower alkyl; lower alkenyl; aryl,heteroaryl; or aryl-lower alkyl; R⁶³ is H; lower alkyl; lower alkenyl;aryl, heteroaryl; aryl-lower alkyl; heteroaryl-lower alkyl; —COR⁶⁴;—COOR⁵⁷; —CONR⁵⁸R⁵⁹; —SO₂R⁶²; or —PO(OR⁶⁰)₂; or R³⁴ and R⁶³ takentogether can form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S (CH₂)₂—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; R⁶⁴ is H; lower alkyl; lower alkenyl; aryl;heteroaryl; aryl-lower alkyl; heteroaryl-lower alkyl;—(CH₂)_(p)(CHR⁶¹)_(s)OR⁶⁵; —(CH₂)_(p)(CHR⁶¹)_(s)SR⁶⁶;—(CH₂)_(p)(CHR⁶¹)_(s)NR³⁴R⁶³; —(CH₂)_(p)(CHR⁶¹)_(s)OCONR⁷⁸R⁸²; or—(CH₂)_(p)(CHR⁶¹)_(s)NR²⁰CONR⁷⁸R⁸²; R⁶⁵ is H; lower alkyl; loweralkenyl; aryl, aryl-lower alkyl; heteroaryl-lower alkyl; —COR⁵⁷;—COOR⁵⁷; or —CONR⁵⁸R⁵⁹; R⁶⁶ is H; lower alkyl; lower alkenyl; aryl;aryl-lower alkyl; heteroaryl-lower alkyl; or —CONR⁵⁸R⁵⁹; R⁶⁷ is H; Cl;Br; F; NO₂; —NR³⁴COR⁵⁷; —CF₃; CN; —OCF₃; —OCHF₂; —OR⁵⁷; —SR⁶²; loweralkyl; or lower alkenyl; R⁶⁸ is H; Cl; Br; F; NO₂; —NR³⁴COR⁵⁷; —CF₃; CN;—OCF₃; —OCHF₂; —OR⁵⁷; —SR⁶²; lower alkyl; or lower alkenyl; R⁶⁹ is H;Cl; Br; F; NO₂; —NR³⁴COR⁵⁷; —CF₃; CN; —OCF₃; —OCHF₂; —OR⁵⁷; —SR⁶²; loweralkyl; or lower alkenyl; R⁷⁰ is H; Cl; Br; F; NO₂; —NR³⁴COR⁵⁷; —CF₃; CN;—OCF₃; —OCHF₂; —OR⁵⁷; —SR⁶²; lower alkyl; or lower alkenyl; R⁷¹ is loweralkyl; lower alkenyl; —(CH₂)_(p)(CHR⁶¹)_(s)OR⁷⁵;—(CH₂)_(p)(CHR⁶¹)_(s)SR⁷⁵; —(CH₂)_(p)(CHR⁶¹)_(s)NR³³R³⁴;—(CH₂)_(p)(CHR⁶¹)_(s)OCONR³³R⁷⁵; —(CH₂)_(p)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²;—(CH₂)_(o)(CHR⁶¹)_(s)COOR⁷⁵; —(CH₂)_(p)CONR⁵⁸R⁵⁹; —(CH₂)_(p)PO(OR⁶²)₂;—(CH₂)_(p)SO₂R⁶²; or —(CH₂)_(o)—C₆R⁶⁷R⁶⁸R⁶⁹R⁷⁰R⁷⁶; R⁷² is alkyl;alkenyl; —(CH₂)_(p)(CHR⁶¹)_(s)OR⁸⁵; or —(CH₂)_(p)(CHR⁶¹)_(s)SR⁸⁵; R⁷³ is—(CH₂)_(o)R⁷⁷; —(CH₂)_(r)O(CH₂)_(o)R⁷⁷; —(CH₂)_(r)S(CH₂)_(o)R⁷⁷; or—(CH₂)_(r)NR²⁰(CH₂)_(o)R⁷⁷; R⁷⁴ is —(CH₂)_(p)NR⁷⁸R⁷⁹; —(CH₂)_(p)NR⁷⁷R⁸⁰;—(CH₂)_(p)C(═NR⁸⁰)NR⁷⁸R⁷⁹; —(CH₂)_(p)C(═NOR⁵⁰)NR⁷⁸R⁷⁹;—(CH₂)_(p)C(═NNR⁷⁸R⁷⁹)NR⁷⁸R⁷⁹; —(CH₂)_(p)NR⁸⁰C(═NR⁸⁰)NR⁷⁸R⁷⁹;—(CH₂)_(p)N═C(NR⁷⁸R⁸⁰)NR⁷⁹R⁸⁰; —(CH₂)_(p)C₆H₄NR⁷⁸R⁷⁹;—(CH₂)_(p)C₆H₄NR⁷⁷R⁸⁰; —(CH₂)_(p)C₆H₄C(═NR⁸⁰)NR⁷⁸R⁷⁹;—(CH₂)_(p)C₆H₄C(═NOR⁵⁰)NR⁷⁸R⁷⁹; —(CH₂)_(p)C₆H₄C(═NNR⁷⁸R⁷⁹)NR⁷⁸R⁷⁹;—(CH₂)_(p)C₆H₄NR⁸⁰C(═NR⁸⁰) NR⁷⁸R⁷⁹; —(CH₂)_(p)C₆H₄N═C(NR⁷⁸R⁸⁰)NR⁷⁹R⁸⁰;—(CH₂)_(r)O(CH₂)_(m)NR⁷⁸R⁷⁹; —(CH₂)_(r)O(CH₂)_(m)NR⁷⁷R⁸⁰;—(CH₂)_(r)O(CH₂)_(p)C(═NR⁸⁰)NR⁷⁸R⁷⁹;—(CH₂)_(r)O(CH₂)_(p)C(═NOR⁵⁰)NR⁷⁸R⁷⁹; —(CH₂)_(r)O(CH₂)_(p)C(═NNR⁷⁸R⁷⁹)NR⁷⁸R⁷⁹; —(CH₂)_(r)O(CH₂)_(m)NR⁸⁰C(═NR⁸⁰)NR⁷⁸R⁷⁹;—(CH₂)_(r)O(CH₂)_(m)N═C(NR⁷⁸R⁸⁰)NR⁷⁹R⁸⁰;—(CH₂)_(r)O(CH₂)_(p)C₆H₄CNR⁷⁸R⁷⁹;—(CH₂)_(r)O(CH₂)_(p)C₆H₄C(═NR⁸⁰)NR⁷⁸R⁷⁹;—(CH₂)_(r)O(CH₂)_(p)C₆H₄C(═NOR⁵⁰)NR⁷⁸R⁷⁹;—(CH₂)_(r)O(CH₂)_(p)C₆H₄C(═NNR⁷⁸R⁷⁹)NR⁷⁸R⁷⁹;—(CH₂)_(r)O(CH₂)_(p)C₆H₄NR⁸⁰C(═NR⁸⁰)NR⁷⁸R⁷⁹;—(CH₂)_(r)S(CH₂)_(m)NR⁷⁸R⁷⁹; —(CH₂)_(r)S(CH₂)_(m)NR⁷⁷R⁸⁰;—(CH₂)_(r)S(CH₂)_(p)C(═NR⁸⁰)NR⁷⁸R⁷⁹;—(CH₂)_(r)S(CH₂)_(p)C(═NOR⁵⁰)NR⁷⁸R⁷⁹;—(CH₂)_(r)S(CH₂)_(p)C(═NNR⁷⁸R⁷⁹)NR⁷⁸R⁷⁹;—(CH₂)_(r)S(CH₂)_(m)NR⁸⁰C(═NR⁸⁰)NR⁷⁸R⁷⁹;—(CH₂)_(r)S(CH₂)_(m)N═C(NR⁷⁸R⁸⁰)NR⁷⁹R⁸⁰;—(CH₂)_(r)S(CH₂)_(p)C₆H₄CNR⁷⁸R⁷⁹;—(CH₂)_(r)S(CH₂)_(p)C₆H₄C(═NR⁸⁰NR⁷⁸R⁷⁹;—(CH₂)_(r)S(CH₂)_(p)C₆H₄C(═NOR⁵⁰)NR⁷⁸R⁷⁹;—(CH₂)_(r)S(CH₂)_(p)C₆H₄C(═NNR⁷⁸R⁷⁹)NR⁷⁸R⁷⁹;—(CH₂)_(r)S(CH₂)_(p)C₆H₄NR⁸⁰C(═NR⁸⁰)NR⁷⁸R⁷⁹; —(CH₂)_(p)NR⁸⁰COR⁶⁴;—(CH₂)_(p)NR⁸⁰COR⁷⁷; —(CH₂)_(p)NR⁸⁰CONR⁷⁸R⁷⁹; or—(CH₂)_(p)C₆H₄NH⁸⁰CONR⁷⁸H⁷⁹; R⁷⁵ is lower alkyl; lower alkenyl; oraryl-lower alkyl; or R³³ and R⁷⁵ taken together can form: —(CH₂)₂₋₆—;—(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; or R⁷⁵ and R⁸²taken together can form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—;or —(CH₂)₂NR⁵⁷(CH₂)₂—; R⁷⁶ is H; lower alkyl; lower alkenyl; aryl-loweralkyl; —(CH₂)_(o)OR⁷²; —(CH₂)_(o)SR⁷²; —(CH₂)_(o)NR³³R³⁴;—(CH₂)_(o)OCONR³³R⁷⁵; —(CH₂)_(o)NR²⁰CONR³³R⁸¹; —(CH₂)_(o)COOR⁷⁵;—(CH₂)_(o)CONR⁵⁸R⁵⁹; —(CH₂)_(o)PO(OR⁶⁰)₂; —(CH₂)_(p)SO₂R⁶²; or—(CH₂)_(o)COR⁶⁴; R⁷⁷ is —C₆R⁶⁷R⁶⁸R⁶⁹R⁷⁰R⁷⁶ with the proviso that atleast two of R⁶⁷, R⁶⁹, R⁶⁹ and R⁷⁰ are H; or a heteroaryl group of oneof the formulae

R⁷⁸ is H; lower alkyl; aryl; or aryl-lower alkyl; or R⁷⁸ and R⁸² takentogether can form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; R⁷⁹ is H; lower alkyl; aryl; or aryl-lower alkyl; orR⁷⁸ and R⁷⁹, taken together, can be —(CH₂)₂₋₇—; —(CH₂)₂O(CH₂)₂—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; R⁸⁰ is H; or lower alkyl; R⁸¹ is H; lower alkyl; oraryl-lower alkyl; R³³ and R⁸¹ taken together can form: —(CH₂)₂₋₆—;—(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; R⁸² is H; —CF₃;—OCF₃; —OCHF₂; lower alkyl; aryl; heteroaryl; or aryl-lower alkyl; R⁸³is H; lower alkyl; aryl; or —NR⁷⁸R⁷⁹; R⁸⁴ is —(CH₂)_(p)(CHR⁶¹)_(S)OH;—(CH₂)_(p)COOR⁸⁰; —(CH₂)_(p)(CHR⁶¹)_(s)SH; —(CH₂)_(p)CONR⁷⁸R⁷⁹;—(CH₂)_(p)NR⁸⁰CONR⁷⁸R⁷⁹; —(CH₂)_(p)C₆H₄CONR⁷⁸R⁷⁹; or—(CH₂)_(p)C₆H₄NR⁸⁰CONR⁷⁸R⁷⁹; R⁸⁵ is lower alkyl; or lower alkenyl; m is2-4; o is 0-4; p is 1-4; q is 0-2; r is 1 or 2; s is 0 or 1; Z is achain of 14 α-amino and/or α-hydroxy acid residues, the positions ofsaid amino and/or hydroxy acid residues in said chain being countedstarting from the N-terminal amino acid or O-terminal hydroxy acid,whereby these amino or hydroxy acid residues are, depending on theirposition in the chains, Gly, a Glycolic acid residue, Pro, -A-CO—, or ofone of the types C: —NR²⁰CH(R⁷²)CO—; D: —NR²⁰CH(R⁷³)CO—; E:—NR²⁰CH(R⁷⁴)CO—; F: —NR²⁰CH(R⁸⁴)CO—; H:—NR²⁰—CH(CO—)—(CH₂)₄₋₇—CH(CO—)—NR²⁰—;—NR²⁰—CH(CO—)—(CH₂)_(p)SS(CH₂)_(p)—CH(CO—)—NR²⁰—;—NR²⁰—CH(CO—)—(—(CH₂)_(p)NR²⁰CO(CH₂)_(p)—CH(CO—)—NR²⁰—; or—NR²⁰—CH(CO—)—(—(CH₂)_(p)NR²⁰CONR²⁰(CH₂)_(p)—CH(CO—)—NR²⁰—; and—O—CH(R⁷¹)CO—; —O—CH(P⁷²)CO—; —O—CH(R⁷³)CO—; —OCH(R⁷⁴)CO—; or—OCH(R⁸⁴)CO—; with the proviso that in said chain Z of 14 α-amino and/orα-hydroxy acid residues the amino or hydroxy acid residues in positions1 to 14 are: P1: of type C, type D, type F or of type L; P2: of type D,type E, type F, or of type L; P3: of type C, type D, type E, type F,type L, or Gly, or a Glycolic acid residue; P4: of type C, type D, typeE or of type F; P5: of type E, type F or of type L; P6: of type C, typeL, Gly or a Glycolic acid residue; P7: of formula -A-CO—, Pro, Gly or aGlycolic acid residue; P8: of formula A-CO—, type C, type D, type E,type F or of type L; P9: of type D or type E; P10: of type C or type D;P11: of type C, type D or type F; P12: of type D, type F or of type L;P13: of type C, type D, type E, type F or of type L; and P14: of type C,type E, type F or of type L; or P4 and P11, taken together, can form agroup of type H; at P5, P7 and P13 also D-isomers being possible; andwith the further proviso that the molecule contains at least one but notmore than 3 α-hydroxy acid residues; and pharmaceutically acceptablesalts thereof.
 2. Compounds according to claim 1 wherein

is a group of formula (a1) or (a2).
 3. Compounds according to claim 2wherein A is a group of one of the formulae A1 to A69 and A105; R¹ ishydrogen or lower alkyl; R² is H; lower alkyl; lower alkenyl;—(CH₂)_(m)OR⁵⁵ (where R⁵⁵ is lower alkyl; or lower alkenyl);—CH₂)_(m)SR⁵⁶ (where R⁵⁶ is lower alkyl; or lower alkenyl);—(CH₂)_(m)NR³³R³⁴ (where R³³ is lower alkyl; or lower alkenyl; R³⁴ is H;or lower alkyl; or R³³ and R³⁴ taken together are —(CH₂)₂₋₆—;—(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H;or lower alkyl); —(CH₂)_(m)OCONR³³R⁷⁵ (where R³³ is H; lower alkyl; orlower alkenyl; R⁷⁵ is lower alkyl; or R³³ and R⁷⁵ taken together are—(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—;where R⁵⁷ is H; or lower alkyl); —(CH₂)_(m)NR²⁰CONR³³R⁸¹ (where R²⁰ isH; or lower alkyl; R³³ is H; or lower alkyl; or lower alkenyl; R⁸¹ is H;or lower alkyl; or R³³ and R⁸¹ taken together are —(CH₂)₂₋₆—;—(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H;or lower alkyl); —(CH₂)_(o)N(R²⁰)COR⁶⁴ (where: R²⁰ is H; or lower alkyl;R⁶⁴ is lower alkyl; or lower alkenyl); (CH₂)_(o)COOR⁵⁷ (where R⁵⁷ islower alkyl; or lower alkenyl); —(CH₂)_(o)CONR⁵⁶R⁵⁹ (where R⁵⁸ is loweralkyl; or lower alkenyl; and R⁵⁹ is H; or lower alkyl; or R⁵⁸ and R⁵⁹taken together are —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H; or lower alkyl); —(CH₂)_(o)PO(OR⁶⁰)₂(where R⁶⁰ is H; lower alkyl; or lower alkenyl); —(CH₂)_(o)SO₂R⁶² (whereR⁶² is lower alkyl; or lower alkenyl); —(CH₂)_(q)C₆H₄R⁸ (where R⁸ is H;F; Cl; CF₃; lower alkyl; lower alkenyl; or lower alkoxy) or—(CH₂)_(q)CHN₄R⁸; R³ is H; lower alkyl; lower alkenyl; —(CH₂)_(m)OR⁵⁵(where R⁵⁵ is lower alkyl; or lower alkenyl); —(CH₂)_(m)SR⁵⁶ (where R⁵⁶is lower alkyl; or lower alkenyl); —(CH₂)_(m)NR³³R³⁴ (where R³³ is loweralkyl; or lower alkenyl; R³⁴ is H; or lower alkyl; or R³³ and R³⁴ takentogether are —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H; or lower alkyl);—(CH₂)_(m)OCONR³³R⁷⁵ (where R³³ is H; or lower alkyl; or lower alkenyl;R⁷⁵ is lower alkyl; or R³³ and R⁷⁵ taken together are —(CH₂)₂₋₆—;—(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H;or lower alkyl); —(CH₂)_(m)NR²⁰CONR³³R⁸¹ (where R²⁰ is H; or loweralkyl; R³³ is H; or lower alkyl; or lower alkenyl; R⁸¹ is H; or loweralkyl; or R³³ and R⁸¹ taken together are —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;—(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H; or lower alkyl);—(CH₂)_(o)N(R²⁰)COR⁶⁴ (where: R²⁰ is H; or lower alkyl; R⁶⁴ is loweralkyl; or lower alkenyl); —(CH₂)COOR⁵⁷ (where R⁵⁷ is lower alkyl; orlower alkenyl); —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸ is lower alkyl; or loweralkenyl; and R⁵⁹ is H; lower alkyl; or R⁵⁸ and R⁵⁹ taken together are—(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—;where R⁵⁷ is H; or lower alkyl); —(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰ is loweralkyl; or lower alkenyl); —(CH₂)_(o)SO₂R⁶² (where R⁶² is lower alkyl; orlower alkenyl); or —(CH₂)_(q)C₆H₄R⁸ (where R⁸ is H; F; Cl; CF₃; loweralkyl; lower alkenyl; or lower alkoxy); R⁴ is H; lower alkyl; loweralkenyl; —(CH₂)_(m)OR⁵⁵ (where R⁵⁵ is lower alkyl; or lower alkenyl);—(CH₂)_(m)SR⁵⁶ (where R⁵⁶ is lower alkyl; or lower alkenyl);—(CH₂)_(m)NR³³R³⁴ (where R³³ is lower alkyl; or lower alkenyl; R³⁴ is H;or lower alkyl; or R³³ and R³⁴ taken together are —(CH₂)₂₋₆—;—(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H;or lower alkyl); —(CH₂)_(m)OCONR³³R⁷⁵ (where R³³ is H; or lower alkyl;or lower alkenyl; R⁷⁵ is lower alkyl; or R³³ and R⁷⁵ taken together are—(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—;where R⁵⁷ is H; or lower alkyl); —(CH₂)_(m)NR²⁰CONR³³R⁸¹ (where R²⁰ isH; or lower alkyl; R³³ is H; or lower alkyl; or lower alkenyl; R⁸¹ is H;or lower alkyl; or R³³ and R⁸¹ taken together are —(CH₂)₂₋₆—;—(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H;or lower alkyl); —(CH₂)_(m)N(R²⁰)COR⁶⁴ (where: R²⁰ is H; or lower alkyl;R⁶⁴ is lower alkyl; or lower alkenyl); —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷ islower alkyl; or lower alkenyl); —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸ is loweralkyl; or lower alkenyl; and R⁵⁹ is H; or lower alkyl; or R⁵⁸ and R⁵⁹taken together are —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: is H; or lower alkyl);—(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰ is lower alkyl; or lower alkenyl);—(CH₂)_(o)SO₂R⁶² (where R⁶² is lower alkyl; or lower alkenyl); or—(CH₂)_(q)C₆H₄R⁸ (where R⁸ is H; F; Cl; CF₃; lower alkyl; lower alkenyl;or lower alkoxy); R⁵ is lower alkyl; lower alkenyl; —(CH₂)_(o)R⁵⁵ (whereR⁵⁵ is lower alkyl; or lower alkenyl); —(CH₂)_(o)SR⁵⁶ (where R⁵⁶ islower alkyl; or lower alkenyl); (CH₂)_(o)NR³³R³⁴ (where R³³ is loweralkyl; or lower alkenyl; R³⁴ is H; or lower alkyl; or R³³ and R³⁴ takentogether are —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or—(CH₂)₂NR⁵⁷ (CH₂)₂—; where R⁵⁷ is H; or lower alkyl);—(CH₂)_(o)OCONR³³R⁷⁵ (where R³³ is H; or lower alkyl; or lower alkenyl;R⁷⁵ is lower alkyl; or R³³ and R⁷⁵ taken together are —(CH₂)₂₋₆—;—(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H;or lower alkyl); —(CH₂)_(o)NR²⁰CONR³³R⁸¹ (where R²⁰ is H; or lower loweralkyl; R³³ is H; or lower alkyl; or lower alkenyl; R⁸¹ is H; or loweralkyl; or R³³ and R⁸¹ taken together are —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;—(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H; or lower alkyl);—(CH₂)_(o)N(R²⁰)COR⁶⁴ (where: R²⁰ is H; or lower alkyl; R⁶⁴ is alkyl;alkenyl; aryl; aryl-lower alkyl; or heteroaryl-lower alkyl);—(CH₂)_(o)COOR⁵⁷ (where R⁵⁷ is lower alkyl; or lower alkenyl);—(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸ is lower alkyl; or lower alkenyl; and R⁵⁹is H; or lower alkyl; or R⁵⁸ and R⁵⁹ taken together are —(CH₂)₂₋₆—;—(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H;or lower alkyl); —(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰ is lower alkyl; or loweralkenyl); —(CH₂)_(o)SO₂R⁶² (where R⁶² is lower alkyl; or lower alkenyl);or —(CH₂)_(q)C₆H₄R⁸ (where R⁸ is H; F; Cl; CF₃; lower alkyl; loweralkenyl; or lower alkoxy); R⁶ is H; lower alkyl; lower alkenyl;—(CH₂)_(o)OR⁵⁵ (where R⁵⁵ is lower alkyl; or lower alkenyl);—(CH₂)_(o)SR⁵⁶ (where R⁵⁶ is lower alkyl; or lower alkenyl);—(CH₂)_(o)NR³³R³⁴ (where R³³ is lower alkyl; or lower alkenyl; R³⁴ is H;or lower alkyl; or R³³ and R³⁴ taken together are —(CH₂)₂₋₆—;—(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H;or lower alkyl); —(CH₂)_(o)OCONR³³R⁷⁵ (where R³³ is H; or lower alkyl;or lower alkenyl; R⁷⁵ is lower alkyl; or R³³ and R⁷⁵ taken together are—(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—;where R⁵⁷ is H; or lower alkyl); —(CH₂)_(o)NR²⁰CONR³³R⁸¹ (where R²⁰ isH; or lower lower alkyl; R³³ is H; or lower alkyl; or lower alkenyl; R⁸¹is H; or lower alkyl; or R³³ and R⁸¹ taken together are —(CH₂)₂₋₆—;—(CH₂)₂O(CH₂)—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H;or lower alkyl); —(CH₂)_(o)N(R²⁰)COR⁶⁴ (where R²⁰ is H; or lower alkyl;R⁶⁴ is lower alkyl; or lower alkenyl); —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷ islower alkyl; or lower alkenyl); —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸ is loweralkyl; or lower alkenyl; and R⁵⁹ is H; or lower alkyl; or R⁵⁸ and R⁵⁹taken together are —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H; or lower alkyl); —(CH₂)_(o)PO(OR⁶⁰)₂(where R⁶⁰ is lower alkyl; or lower alkenyl); —(CH₂)_(o)SO₂R⁶² (whereR⁶² is lower alkyl; or lower alkenyl); or —(CH₂)_(q)C₆H₄R⁸ (where R⁸ isH; F; Cl; CF₃; lower alkyl; lower alkenyl; or lower alkoxy); R⁷ is loweralkyl; lower alkenyl; —(CH₂)_(q)OR⁵⁵ (where R⁵⁵ is lower alkyl; or loweralkenyl); —(CH₂)_(q)SR⁵⁶ (where R⁵⁶ is lower alkyl; or lower alkenyl);—(CH₂)_(q)NR³³R³⁴ (where R³³ is lower alkyl; or lower alkenyl; R³⁴ is H;or lower alkyl; or R³³ and R³⁴ taken together are —(CH₂)₂₋₆—;—(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H;or lower alkyl); —(CH₂)_(q)OCONR³³R⁷⁵ (where R³³ is H; or lower alkyl;or lower alkenyl; R⁷⁵ is lower alkyl; or R³³ and R⁷⁵ taken together are—(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—;where R⁵⁷ is H; or lower alkyl); —(CH₂)_(q)NR²⁰CONR³³R⁸¹ (where R²⁰ isH; or lower alkyl; R³³ is H; or lower alkyl; or lower alkenyl; R⁵¹ is H;or lower alkyl; or R³³ and R⁸¹ taken together are —(CH₂)₂₋₆—;—(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H;or lower alkyl); —(CH₂)_(q)N(R²⁰)COR⁶⁴ (where: R²⁰ is H; or lower alkyl;R⁶⁴ is lower alkyl; or lower alkenyl); —(CH₂)_(r)COOR⁵⁷ (where R⁵⁷ islower alkyl; or lower alkenyl); —(CH₂)_(q)CONR⁵⁸R⁵⁹ (where R⁵⁸ is loweralkyl; or lower alkenyl; and R⁵⁹ is H; or lower alkyl; or R⁵⁸ and R⁵⁹taken together are —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂ 13 ; or—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H; or lower alkyl); —(CH₂)_(r)PO(OR⁶⁰)₂(where R⁶⁰ is lower alkyl; or lower alkenyl); —(CH₂)_(r)SO₂R⁶² (whereR⁶² is lower alkyl; or lower alkenyl); or —(CH₂)_(q)C₆H₄R⁸ (where R⁸ isH; F; Cl; CF₃; lower alkyl; lower alkenyl; or lower alkoxy); R⁸ is H; F;Cl; CF₃; lower alkyl; lower alkenyl; —(CH₂)_(o)OR⁵⁵ (where R⁵⁵ is loweralkyl; or lower alkenyl); —(CH₂)_(o)SR⁵⁶ (where R⁵⁶ is lower alkyl; orlower alkenyl); —(CH₂)_(o)NR³³R³⁴ (where R³³ is lower alkyl; or loweralkenyl; R³⁴ is H; or lower alkyl; or R³³ and R³⁴ taken together are—(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—;where R⁵⁷ is H; or lower alkyl); —(CH₂)_(o)OCONR³³R⁷⁵ (where R³³ is H;or lower alkyl; or lower alkenyl; R⁷⁵ is lower alkyl; or R³³ and R⁷⁵taken together are —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H; or lower alkyl);—(CH₂)_(o)NR²⁰CONR³³R⁸¹ (where R²⁰ is H; or lower alkyl; R³³ is H; orlower alkyl; or lower alkenyl; R⁸¹ is H; or lower alkyl; or R³³ and R⁸¹taken together are —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H; or lower alkyl);—(CH₂)_(o)N(R²⁰)COR⁶⁴ (where R²⁰ is H; or lower alkyl; R⁶⁴ is loweralkyl; or lower alkenyl); —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷ is lower alkyl; orlower alkenyl); —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸ is lower alkyl; or loweralkenyl; and R⁵⁹ is H; or lower alkyl; or R⁵⁸ and R⁵⁹ taken together are—(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—;where R⁵⁷ is H; or lower alkyl); —(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰ is loweralkyl; or lower alkenyl); —(CH₂)_(o)SO₂R⁶² (where R⁶² is lower alkyl; orlower alkenyl); or —(CH₂)_(q)C₆H₄R⁸ (where R⁸ is H; F; Cl; CF₃; loweralkyl; lower alkenyl; or lower alkoxy); R⁹ is lower alkyl; loweralkenyl; —(CH₂)_(o)OR⁵⁵ (where R⁵⁵ is lower alkyl; or lower alkenyl);—(CH₂)_(o)SR⁵⁶ (where R⁵⁶ is lower alkyl; or lower alkenyl);—(CH₂)_(o)NR³³R³⁴ (where R³³ is lower alkyl; or lower alkenyl; R³⁴ is H;or lower alkyl; or R³³ and R³⁴ taken together are —(CH₂)₂₋₆—;—(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H;or lower alkyl); —(CH₂)_(o)OCONR³³R⁷⁵ (where R³³ is H; or lower alkyl;or lower alkenyl; R⁷⁵ is lower alkyl; or R³³ and R⁷⁵ taken together are—(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—;where R⁵⁷ is H; or lower alkyl); —(CH₂)_(m)NR²⁰CONR³³R⁸¹ (where R²⁰ isH; or lower lower alkyl; R³³ is H; or lower alkyl; or lower alkenyl; R⁸¹is H; or lower alkyl; or R³³ and R⁸¹ taken together are —(CH₂)₂₋₆—;—(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H;or lower alkyl); —(CH₂)_(o)N(R²⁰)COR⁶⁴ (where R²⁰ is H; or lower alkyl;R⁶⁴ is lower alkyl; or lower alkenyl); —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷ islower alkyl; or lower alkenyl); —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸ is loweralkyl; or lower alkenyl; and R⁵⁹ is H; or lower alkyl; or R⁵⁸ and R⁵⁹taken together are —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H; or lower alkyl); —(CH₂)_(o)PO(OR⁶⁰)₂(where R⁶⁰ is lower alkyl; or lower alkenyl); —(CH₂)_(o)SO₂R⁶² (whereR⁶² is lower alkyl; or lower alkenyl); or —(CH₂)_(q)C₆H₄R⁸ (where R⁸ isH; F; Cl; CF₃; lower alkyl; lower alkenyl; or lower alkoxy); R¹⁰ islower alkyl; lower alkenyl; —(CH₂)_(o)OR⁵⁵ (where R⁵⁵ is lower alkyl; orlower alkenyl); —(CH₂)_(o)SR⁵⁶ (where R⁵⁶ is lower alkyl; or loweralkenyl); —(CH₂)_(o)NR³³R³⁴ (where R³³ is lower alkyl; or lower alkenyl;R³⁴ is H; or lower alkyl; or R³³ and R³⁴ taken together are —(CH₂)₂₋₆—;—(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H;or lower alkyl); —(CH₂)_(o)OCONR³³R⁷⁵ (where R³³ is H; or lower alkyl;or lower alkenyl; R⁷⁵ is lower alkyl; or R³³ and R⁷⁵ taken together are—(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—;where R⁵⁷: H is or lower alkyl); —(CH₂)_(o)NR²⁰CONR³³R⁸¹ (where R²⁰ isH; or lower lower alkyl; R³³ is H; or lower alkyl; or lower alkenyl; R⁸¹is H; or lower alkyl; or R³³ and R⁸¹ taken together are —(CH₂)₂₋₆—;—(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H;or lower alkyl); —(CH₂)_(o)N(R²⁰)COR⁶⁴ (where R²⁰ is H; or lower alkyl;R⁶⁴ is lower alkyl; or lower alkenyl); —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷ islower alkyl; or lower alkenyl); —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸ is loweralkyl; or lower alkenyl; and R⁵⁹ is H; lower alkyl; or R⁵⁸ and R⁵⁹ takentogether are —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H; or lower alkyl); —(CH₂)_(o)PO(OR⁶⁰)₂(where R⁶⁰ is lower alkyl; or lower alkenyl); —(CH₂)_(o)SO₂R⁶² (whereR⁶² is lower alkyl; or lower alkenyl); or —(CH₂)_(q)C₆H₄R⁸ (where R⁸ isH; F; Cl; CF₃; lower alkyl; lower alkenyl; or lower alkoxy); R¹¹ is H;lower alkyl; lower alkenyl; —(CH₂)_(m)OR⁵⁵ (where R⁵⁵ is lower alkyl; orlower alkenyl); —(CH₂)_(m)SR⁵⁶ (where R⁵⁶ is lower alkyl; or loweralkenyl); —(CH₂)_(m)NR³³R³⁴ (where R³³ is lower alkyl; or lower alkenyl;R³⁴ is H; or lower alkyl; or R³³ and R³⁴ taken together are —(CH₂)₂₋₆—;—(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H;or lower alkyl); —(CH₂)_(m)OCONR³³R⁷⁵ (where R³³ is H; or lower alkyl;or lower alkenyl; R⁷⁵ is lower alkyl; or R³³ and R⁷⁵ taken together are—(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—;where R⁵⁷ is H; or lower alkyl); —(CH₂)_(m)NR²⁰CONR³³R⁸¹ (where R²⁰ isH; or lower alkyl; R³³ is H; or lower alkyl; or lower alkenyl; R⁸¹ is H;or lower alkyl; or R³³ and R⁸¹ taken together are —(CH₂)₂₋₆—;—(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H;or lower alkyl); —(CH₂)_(m)N(R²⁰)COR⁶⁴ (where R²⁰ is H; or lower alkyl;R⁶⁴ is lower alkyl; or lower alkenyl); —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷ islower alkyl; or lower alkenyl); —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸ is loweralkyl; or lower alkenyl; and R⁵⁹ is H; lower alkyl; or R⁵⁸ and R⁵⁹ takentogether are —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H; or lower alkyl); —(CH₂)_(o)PO(OR⁶⁰)₂(where R⁶⁰ is lower alkyl; or lower alkenyl); —(CH₂)_(o)SO₂R⁶² (whereR⁶² is lower alkyl; or lower alkenyl); or —(CH₂)_(q)C₆H₄R⁸ (where R⁸ isH; F; Cl; CF₃; lower alkyl; lower alkenyl; or lower alkoxy); R¹² is H;lower alkyl; lower alkenyl; —(CH₂)_(m)OR⁵⁵ (where R⁵⁵ is lower alkyl; orlower alkenyl); —(CH₂)_(m)SR⁵⁶ (where R⁵⁶ is lower alkyl; or loweralkenyl); —(CH₂)_(m)NR³³R³⁴ (where R³³ is lower alkyl; or lower alkenyl;R³⁴ is H; or lower alkyl; or R³³ and R³⁴ taken together are —(CH₂)₂₋₆—;—(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H;or lower alkyl); —(CH₂)_(m)OCONR³³R⁷⁵ (where R³³ is H; or lower alkyl;or lower alkenyl; R⁷⁵ is lower alkyl; or R³³ and R⁷⁵ taken together are—(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—;where R⁵⁷ is H; or lower alkyl); —(CH₂)_(m)NR²⁰CONR³³R⁸¹ (where R²⁰ isH; or lower lower alkyl; R³³ is H; or lower alkyl; or lower alkenyl; R⁸¹is H; or lower alkyl; or R³³ and R⁸¹ taken together are —(CH₂)₂₋₆—;—(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H;or lower alkyl); —(CH₂)_(m)N(R²⁰)COR⁶⁴ (where: R²⁰ is H; or lower alkyl;R⁶⁴ is lower alkyl; or lower alkenyl); —(CH₂)_(r)COOR⁵⁷ (where R⁵⁷ islower alkyl; or lower alkenyl); —(CH₂)_(r)CONR⁵⁸R⁵⁹ (where R⁵⁸ is loweralkyl; or lower alkenyl; and R⁵⁹ is H; or lower alkyl; or R⁵⁸ and R⁵⁹taken together are —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H; or lower alkyl); —(CH₂)_(r)PO(OR⁶⁰)₂(where R⁶⁰ ) is lower alkyl; or lower alkenyl); —(CH₂)_(o)SO₂R⁶² (whereR⁶² is lower alkyl; or lower alkenyl); or —(CH₂)_(q)C₆H₄R⁸ (where R⁸ isH; F; Cl; CF₃; lower alkyl; lower alkenyl; or lower alkoxy); R¹³ islower alkyl; lower alkenyl; —(CH₂)_(q)OR⁵⁵ (where R⁵⁵ is lower alkyl; orlower alkenyl); —(CH₂)_(q)SR⁵⁶ (where R⁵⁶ is lower alkyl; or loweralkenyl); —(CH₂)_(q)NR³³R³⁴ (where R³³ is lower alkyl; or lower alkenyl;R³⁴ is H; or lower alkyl; or R³³ and R³⁴ taken together are —(CH₂)₂₋₆—;—(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H;or lower alkyl); —(CH₂)_(q)OCONR³³R⁷⁵ (where R³³ is H; or lower alkyl;or lower alkenyl; R⁷⁵ is lower alkyl; or R³³ and R⁷⁵ taken together are—(CH₂)₂₋₆—: —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—;where R⁵⁷ is H; or lower alkyl); —(CH₂)_(q)NR²⁰CONR³³R⁸¹ (where R²⁰ isH; or lower lower alkyl; R³³ is H; or lower alkyl; or lower alkenyl; R⁸¹is H; or lower alkyl; or R³³ and R⁸¹ taken together are —(CH₂)₂₋₆—;—(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H;or lower alkyl); —(CH₂)_(q)N(R²⁰)COR⁶⁴ (where: R²⁰ is H; or lower alkyl;R⁶⁴ is lower alkyl; or lower alkenyl); —(CH₂)_(r)COOR⁵⁷ (where R⁵⁷ islower alkyl; or lower alkenyl); —(CH₂)_(q)CONR⁵⁸R⁵⁹ (where R⁵⁸ is loweralkyl; or lower alkenyl; and R⁵⁹ is H; or lower alkyl; or R⁵⁸ and R⁵⁹taken together are —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H; or lower alkyl); —(CH₂)_(r)PO(OR⁶⁰)₂(where R⁶⁰ is lower alkyl; or lower alkenyl); —(CH₂)_(r)SO₂R⁶² (whereR⁶² is lower alkyl; or lower alkenyl); or —(CH₂)_(q)C₆H₄R⁸ (where R⁸ isH; F; Cl; CF₃; lower alkyl; lower alkenyl; or lower alkoxy); R¹⁴ is H;lower alkyl; lower alkenyl; —(CH₂)_(m)OR⁵⁵ (where R⁵⁵ is lower alkyl; orlower alkenyl); —(CH₂)_(m)SR⁵⁶ (where R⁵⁶ is lower alkyl; or loweralkenyl); —(CH₂)_(m)NR³³R³⁴ (where R³³ is lower alkyl; or lower alkenyl;R³⁴ is H; or lower alkyl; or R³³ and R³⁴ taken together are —(CH₂)₂₋₆—;—(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H;or lower alkyl); —(CH₂)_(m)OCONR³³R⁷⁵ (where R³³ is H; or lower alkyl;or lower alkenyl; R⁷⁵ is lower alkyl; or R³³ and R⁷⁵ taken together are—(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—;where R⁵⁷ is H; or lower alkyl); —(CH₂)_(m)NR²⁰CONR³³R¹⁸ (where R²⁰ isH; or lower lower alkyl; R³³ is H; or lower alkyl; or lower alkenyl isR⁸¹: H; or lower alkyl; or R³³ and R⁸¹ taken together are —(CH₂)₂₋₆—;—(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H;or lower alkyl); —(CH₂)_(m)N(R²⁰)COR⁶⁴ (where: R²⁰ is H; lower alkyl;R⁶⁴ is lower alkyl; or lower alkenyl); —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷ islower alkyl; or lower alkenyl); —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸ is loweralkyl; or lower alkenyl; and R⁵⁹ is H; or lower alkyl; or R⁵⁸ and R⁵⁹taken together are —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H; or lower alkyl); —(CH₂)_(o)PO(OR⁶⁰)₂(where R⁶⁰ is lower alkyl; or lower alkenyl); —(CH₂)_(o)SO₂R⁶² (whereR⁶² is lower alkyl; or lower alkenyl); or —(CH₂)_(q)C₆H₄R⁸ (where R⁸ isH; F; Cl; CF₃; lower alkyl; lower alkenyl; or lower alkoxy); R¹⁵ islower alkyl; lower alkenyl; —(CH₂)_(o)OR⁵⁵ (where R⁵⁵ is lower alkyl; orlower alkenyl); —(CH₂)_(o)SR⁵⁶ (where R⁵⁶ is lower alkyl; or loweralkenyl); —(CH₂)_(o)NR³³R³⁴ (where R³³ is lower alkyl; or lower alkenyl;R³⁴ is H; or lower alkyl; or R³³ and R³⁴ taken together are —(CH₂)₂₋₆—;—(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H;or lower alkyl); —(CH₂)_(o)OCONR³³R⁷⁵ (where R³³ is H; or lower alkyl;or lower alkenyl; R⁷⁵ is lower alkyl; or R³³ and R⁷⁵ taken together are—(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—;where R⁵⁷ is H; or lower alkyl); —(CH₂)_(o)NR²⁰CONR³³R⁸¹ (where R²⁰ isH; or lower lower alkyl; R³³ is H; or lower alkyl; or lower alkenyl; R⁸¹is H; or lower alkyl; or R³³ and R⁸¹ taken together are —(CH₂)₂₋₆—;—(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H;or lower alkyl); —(CH₂)_(o)N(R²⁰)COR⁶⁴ (where R²⁰ is H; or lower alkyl;R⁶⁴ is lower alkyl; or lower alkenyl); —NR²⁰CO lower alkyl (R²⁰═H; orlower alkyl); being particularly favoured; —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷is lower alkyl; or lower alkenyl); —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸ islower alkyl, or lower alkenyl; and R⁵⁹ is H; lower alkyl; or R⁵⁸ and R⁵⁹taken together are —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H; or lower alkyl); —(CH₂)_(o)PO(OR⁶⁰)₂(where R⁶⁰ is lower alkyl; or lower alkenyl); —(CH₂)_(o)SO₂R⁶² (whereR⁶² is lower alkyl; or lower alkenyl); or (CH₂)_(q)C₆H₄R⁹ (where R⁸ isH; F; Cl; CF₃; lower alkyl; lower alkenyl; or lower alkoxy); R¹⁶ islower alkyl; lower alkenyl; —(CH₂)_(o)OR⁵⁵ (where R⁵⁵ is lower alkyl; orlower alkenyl); —(CH₂)_(o)SR⁵⁶ (where R⁵⁶ is lower alkyl; or loweralkenyl); —(CH₂)_(o)NR³³R³⁴ (where R³³ is lower alkyl; or lower alkenyl;R³⁴ is H; or lower alkyl; or R³³ and R³⁴ taken together are —(CH₂)₂₋₆—;—(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H;or lower alkyl); —(CH₂)_(o)OCONR⁷⁵ (where R³³ is H; or lower alkyl; orlower alkenyl; R⁷⁵ is lower alkyl; or R³³ and R⁷⁵ taken together are—(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—;where R⁵⁷ is H; or lower alkyl); —(CH₂)_(o)NR²⁰CONR³³R⁸¹ (where R²⁰ isH; or lower lower alkyl; R³³ is H; or lower alkyl; or lower alkenyl; R⁸¹is H; or lower alkyl; or R³³ and R⁸¹ taken together are —(CH₂)₂₋₆—:—(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H;or lower alkyl); —(CH₂)_(o)N(R²⁰)COR⁶⁴ (where R²⁰ is H; or lower alkyl;R⁶⁴ is lower alkyl; or lower alkenyl); —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷ islower alkyl; or lower alkenyl); —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸ is loweralkyl; or lower alkenyl; and R⁵⁹ is H; or lower alkyl; or R⁵⁸ and R⁵⁹taken together are —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H; or lower alkyl); —(CH₂)_(o)PO(OR⁶⁰)₂(where R⁶⁰ is lower alkyl; or lower alkenyl); —(CH₂)_(o)SO₂R⁶² (whereR⁶² is lower alkyl; or lower alkenyl); or —(CH₂)_(q)C₆H₄R⁸ (where R⁸ isH; F; Cl; CF₃; lower alkyl; lower alkenyl; or lower alkoxy); and R¹⁷ islower alkyl; lower alkenyl; —(CH₂)_(q)OR⁵⁵ (where R⁵⁵ is lower alkyl; orlower alkenyl); —(CH₂)_(q)SR⁵⁶ (where R⁵⁶ is lower alkyl; or loweralkenyl); —(CH₂)_(q)NR³³R³⁴ (where R³³ is lower alkyl; or lower alkenyl;R³⁴ is H; or lower alkyl; or R³³ and R³⁴ taken together are —(CH₂)₂₋₆—;—(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H;or lower alkyl); —(CH₂)_(q)OCONR³³R⁷⁵ (where R³³ is H; or lower alkyl;or lower alkenyl; R⁷⁵ is lower alkyl; or R³³ and R⁷⁵ taken together are—(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—;where R⁵⁷ is H; or lower alkyl); —(CH₂)_(q)NR²⁰CONR³³R⁸¹ (where R²⁰ isH; or lower alkyl; R³³ is H; or lower alkyl; or lower alkenyl; R⁸¹ is H;or lower alkyl; or R³³ and R⁸¹ taken together are —(CH₂)₂₋₆—;—(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H;or lower alkyl); —(CH₂)_(q)N(R²⁰)COR⁶⁴ (where: R²⁰ is H; or lower alkyl;R⁶⁴ is lower alkyl; or lower alkenyl); —(CH₂)_(r)COOR⁵⁷ (where R⁵⁷ islower alkyl; or lower alkenyl); —(CH₂)_(q)CONR⁵⁸R⁵⁹ (where R⁵⁸ is loweralkyl; or lower alkenyl; and R⁵⁹ is H; lower alkyl; or R⁵⁸ and R⁵⁹ takentogether are —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H; or lower alkyl); —(CH₂)_(r)PO(OR⁶⁰)₂(where R⁶⁰ is lower alkyl; or lower alkenyl); —(CH₂)_(r)SO₂R⁶² (whereR⁶² is lower alkyl; or lower alkenyl); or —(CH₂)_(q)C₆H₄R⁸ (where R⁸ isH; F; Cl; CF₃; lower alkyl; lower alkenyl; or lower alkoxy). 4.Compounds according to claim 2 or 3 wherein A is a group of one of theformulae A5 (with R² being H); A8; A22; A25; A38 (with R² being H); A42;and A50.
 5. Compounds according to claim 4 wherein A is a group offormula

wherein R²⁰ is H or lower alkyl; and R⁶⁴ is alkyl; alkenyl;—[(CH₂)_(u)—X]_(t)—CH₃, wherein X is —O—; —NR²⁰—, —S—; u=1-3, t=1-6;aryl; aryl-lower alkyl; or heteroaryl-lower alkyl.
 6. Compoundsaccording to claim 5 wherein R⁶⁴ is n-hexyl; n-heptyl; 4-(phenyl)benzyl;diphenylmethyl, 3-amino-propyl; 5-amino-pentyl; methyl; ethyl;isopropyl; isobutyl; n-propyl; cyclohexyl; cyclohexylmethyl; n-butyl;phenyl; benzyl; (3-indolyl)methyl; 2-(3-indolyl)ethyl; (4-phenyl)phenyl;n-nonyl; CH₃—OCH₂CH₂—OCH₂— or CH₃—(OCH₂CH₂)₂—OCH₂—.
 7. Compoundsaccording to claim 2 wherein A is a group of one of the formulae A70 toA104 or A106 to A110; R²⁰ is H; or lower alkyl; R¹⁸ is lower alkyl; R¹⁹is lower alkyl; lower alkenyl; —(CH₂)_(p)OR⁵⁵ (where R⁵⁵ is lower alkyl;or lower alkenyl); —(CH₂)_(p)SR⁵⁶ (where R⁵⁶ is lower alkyl; or loweralkenyl); —(CH₂)_(p)NR³³R³⁴ (where R³³ is lower alkyl; or lower alkenyl;R³⁴ is H; or lower alkyl; or R³³ and R³⁴ taken together are —(CH₂)₂₋₆—;—(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H;or lower alkyl); —(CH₂)_(p)OCONR³³R⁷⁵ (where R³³ is H; or lower alkyl;or lower alkenyl; R⁷⁵ is lower alkyl; or R³³ and R⁷⁵ taken together are—(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—;where R⁵⁷ is H; or lower alkyl); —(CH₂)_(p)NR²⁰CONR³³R⁸¹ (where R²⁰ isH; or lower lower alkyl; R³³ is H; or lower alkyl; or lower alkenyl; R⁸¹is H; or lower alkyl; or R³³ and R⁸¹ taken together are —(CH₂)₂₋₆—;—(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H;or lower alkyl); —(CH₂)_(p)N(R²⁰)COR⁶⁴ (where: R²⁰ is H; or lower alkyl;R⁶⁴ is lower alkyl; or lower alkenyl); (CH₂)_(p)COOR⁵⁷ (where R⁵⁷: loweralkyl; or lower alkenyl); (CH₂)_(p)CONR⁵⁸R⁵⁹ (where R⁵⁸ is lower alkyl;or lower alkenyl; and R⁵⁹ is H; or lower alkyl; or R⁵⁸ and R⁵⁹ takentogether are —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H; or lower alkyl); —(CH₂)_(o)PO(OR⁶⁰)₂(where R⁶⁰ is lower alkyl; or lower alkenyl); —(CH₂)_(p)SO₂R⁶² (whereR⁶² is lower alkyl; or lower alkenyl); or —(CH₂)_(o)C₆H₄R⁸ (where R⁸ isH; F; Cl; CF₃; lower alkyl; lower alkenyl; or lower alkoxy); R²¹ is H;lower alkyl; lower alkenyl; —(CH₂)_(o)OR⁵⁵ (where R⁵⁵ is lower alkyl; orlower alkenyl); —(CH₂)_(o)SR⁵⁶ (where R⁵⁶ is lower alkyl; or loweralkenyl); —(CH₂)_(o)NR³³R³⁴ (where R³³ is lower alkyl; or lower alkenyl;R³⁴ is H; or lower alkyl; or R³³ and R³⁴ taken together are —(CH₂)₂₋₆—;—(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H;or lower alkyl); —(CH₂)_(o)OCONR³³R⁷⁵ (where R³³ is H; or lower alkyl;or lower alkenyl; R⁷⁵ is lower alkyl; or R³³ and R⁷⁵ taken together are—(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—;where R⁵⁷ is H; or lower alkyl); —(CH₂)_(o)NR²⁰CONR³³R⁸¹(where R²⁰ is H;or lower lower alkyl; R³³ is H; or lower alkyl; or lower alkenyl; R⁸¹ isH; or lower alkyl; or R³³ and R⁸¹ taken together are —(CH₂)₂₋₆—;—(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H;or lower alkyl); —(CH₂)_(o)N(R²⁰)COR⁶⁴ (where: R²⁰ is H; or lower alkyl;R⁶⁴ is lower alkyl; or lower alkenyl); —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷ islower alkyl; or lower alkenyl); —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸ is loweralkyl, or lower alkenyl; and R⁵⁹ is H; lower alkyl; or R⁵⁸ and R⁵⁹ takentogether are —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H; or lower alkyl); —(CH₂)_(o)PO(OR⁶⁰)₂(where R⁶⁰ is lower alkyl; or lower alkenyl); —(CH₂)_(o)SO₂R⁶² (whereR⁶² is lower alkyl; or lower alkenyl); or —(CH₂)_(q)C₆H₄R⁸ (where R⁸ isH; F; Cl; CF₃; lower alkyl; lower alkenyl; or lower alkoxy); R²² islower alkyl; lower alkenyl; —(CH₂)_(o)OR⁵⁵ (where R⁵⁵ is lower alkyl; orlower alkenyl); —(CH₂)_(o)SR⁵⁶ (where R⁵⁶ is lower alkyl; or loweralkenyl); —(CH₂)_(o)NR³³R³⁴ (where R³³ is lower alkyl; or lower alkenyl;R³⁴ is H; or lower alkyl; or R³³ and R³⁴ taken together are —(CH₂)₂₋₆—;—(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H;or lower alkyl); —(CH₂)_(o)OCONR³³R⁷⁵ (where R³³ is H; or lower alkyl;or lower alkenyl; R⁷⁵ is lower alkyl; or R³³ and R⁷⁵ taken together are—(CH₂)₂ ₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—;where R⁵⁷ is H; or lower alkyl); —(CH₂)_(o)NR²⁰CONR³³R⁸¹ (where R²⁰ isH; or lower alkyl; R³³ is H; or lower alkyl; or lower alkenyl; R⁸¹ is H;or lower alkyl; or R³³ and R⁸¹ taken together are —(CH₂)₂₋₆—;—(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H;or lower alkyl); —(CH₂)_(o)N(R²⁰)COR⁶⁴ (where R²⁰ is H; or lower alkyl;R⁶⁴ is lower alkyl; or lower alkenyl); —(CH₂)_(o)OCOR⁵⁷ (where R⁵⁷ islower alkyl; or lower alkenyl); —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸ is loweralkyl, or lower alkenyl; and R⁵⁹ is H; lower alkyl; or R⁵⁸ and R⁵⁹ takentogether are —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H; or lower alkyl); —(CH₂)_(o)PO(OR⁶⁰)₂(where R⁶⁰ is lower alkyl; or lower alkenyl); —(CH₂)_(o)SO₂R⁶² (whereR⁶² is lower alkyl; or lower alkenyl); or —(CH₂)_(q)C₆H₄R⁸ (where R⁸ isH; F; Cl; CF; lower alkyl; lower alkenyl; or lower alkoxy); R²³ is H;lower alkyl; lower alkenyl; —(CH₂)_(o)OR⁵⁵ (where R⁵⁵ is lower alkyl; orlower alkenyl); —(CH₂)_(o)SR⁵⁶ (where R⁵⁶ is lower alkyl; or loweralkenyl); —(CH₂)_(o)NR³³R³⁴ (where R³³ is lower alkyl; or lower alkenyl;R³⁴ is H; or lower alkyl; or R³³ and R³⁴ taken together are —(CH₂)₂₋₆—;—(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H;or lower alkyl); —(CH₂)_(o)OCONR³³R⁷⁵ (where R³³ is H; or lower alkyl;or lower alkenyl; R⁷⁵ is lower alkyl; or R³³ and R⁷⁵ taken together are—(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—;where R⁵⁷ is H; or lower alkyl); —(CH₂)_(o)NR²⁰CONR³³R⁸¹ (where R²⁰ isH; or lower alkyl; R³³ is H; or lower alkyl; or lower alkenyl; R⁸¹ is H;or lower alkyl; or R³³ and R⁸¹ taken together are —(CH₂)₂₋₆—;—(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H;or lower alkyl); —(CH₂)_(o)N(R²⁰)COR⁶⁴ (where: R²⁰ is H; or lower alkyl;R⁶⁴ is lower alkyl; or lower alkenyl); —NR²⁰CO-lower alkyl (R²⁰═H; orlower alkyl) being particularly favoured; —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷ islower alkyl; or lower alkenyl); —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸ is loweralkyl, or lower alkenyl; and R⁵⁹ is H; lower alkyl; or R⁵⁸ and R⁵⁹ takentogether are —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H; or lower alkyl); —(CH₂)_(o)PO(OR⁶⁰)₂(where R⁶⁰ is lower alkyl; or lower alkenyl); —(CH₂)_(o)SO₂R⁶² (whereR⁶² is lower alkyl; or lower alkenyl); or —(CH₂)_(q)C₆H₄R⁸ (where R⁸ isH; F; Cl; CF₃; lower alkyl; lower alkenyl; or lower alkoxy); R²⁴ islower alkyl; lower alkenyl; —(CH₂)_(o)OR⁵⁵ (where R⁵⁵ is lower alkyl; orlower alkenyl); —(CH₂)_(o)SR⁵⁶ (where R⁵⁶ is lower alkyl; or loweralkenyl); —(CH₂)_(o)NR³³R³⁴ (where R³³ is lower alkyl; or lower alkenyl;R³⁴ is H; or lower alkyl; or R³³ and R³⁴ taken together are —(CH₂)₂₋₆—;—(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H;or lower alkyl); —(CH₂)_(o)OCONR³³R⁷⁵ (where R³³ is H; or lower alkyl;or lower alkenyl; R⁷⁵ is lower alkyl; or R³³ and R⁷⁵ taken together are—(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—;where R⁵⁷ is H; or lower alkyl); —(CH₂)_(o)NR²⁰CONR³³R⁸¹ (where R²⁰ isH; or lower lower alkyl; R³³ is H; or lower alkyl; or lower alkenyl; R⁸¹is H; or lower alkyl; or R³³ and R⁸¹ taken together are —(CH₂)₂₋₆—;—(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H;or lower alkyl); —(CH₂)_(o)N(R²⁰)COR⁶⁴ (where: R²⁰ is H; or lower alkyl;R⁶⁴ is lower alkyl; or lower alkenyl); —NR²⁰CO-lower alkyl (R²⁰═H; orlower alkyl) being particularly favoured; —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷ islower alkyl; or lower alkenyl); —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸ is loweralkyl, or lower alkenyl; and R⁵⁹ is H; lower alkyl; or R⁵⁸ and R⁵⁹ takentogether are —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H; or lower alkyl); —(CH₂)_(o)PO(OR⁶⁰)₂(where R⁶⁰ is lower alkyl; or lower alkenyl); —(CH₂)_(o)SO₂R⁶² (whereR⁶² is lower alkyl; or lower alkenyl); or —(CH₂)_(q)C₆H₄R⁸ (where R⁸ isH; F; Cl; CF₃; lower alkyl; lower alkenyl; or lower alkoxy); R²⁵ is H;lower alkyl; lower alkenyl; —(CH₂)_(m)OR⁵⁵ (where R⁵⁵ is lower alkyl; orlower alkenyl); —(CH₂)_(m)NR³³R³⁴ (where R³³ is lower alkyl; or loweralkenyl; R³⁴ is H; or lower alkyl; or R³³ and R³⁴ taken together are—(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—;where R⁵⁷ is H; or lower alkyl); —(CH₂)_(m)OCONR³³R⁷⁵ (where R³³ is H;or lower alkyl; or lower alkenyl; R⁷⁵ is lower alkyl; or R³³ and R⁷⁵taken together are —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H; or lower alkyl);—(CH₂)_(m)NR²⁰CONR³³R⁸¹ (where R²⁰ is H; or lower alkyl; R³³ is H; orlower alkyl; or lower alkenyl; R⁸¹ is H; or lower alkyl; or R³³ and R⁸¹taken together are —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H; or lower alkyl);—(CH₂)_(m)N(R²⁰)COR⁶⁴ (where: R²⁰ is H; or lower alkyl; R⁶⁴ is loweralkyl; or lower alkenyl); —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷ is lower alkyl; orlower alkenyl); —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸ is lower alkyl; or loweralkenyl; and R⁵⁹ is H; lower alkyl; or R⁵⁸ and R⁵⁹ taken together are—(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—;where R⁵⁷ is H; or lower alkyl); —(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰ is loweralkyl; or lower alkenyl); —(CH₂)_(o)SO₂R⁶² (where R⁶² is lower alkyl; orlower alkenyl); or —(CH₂)_(q)C₆H₄R⁸ (where R⁸ is H; F; Cl; CF₃; loweralkyl; lower alkenyl; or lower alkoxy); R²⁶ is H; lower alkyl; loweralkenyl; —(CH₂)_(m)OR⁵⁵ (where R⁵⁵ is lower alkyl; or lower alkenyl);—(CH₂)_(m)NR³³R³⁴ (where R³³ is lower alkyl; or lower alkenyl; R³⁴ is H;or lower alkyl; or R³³ and R³⁴ taken together are —(CH₂)₂₋₆—;—(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H;or lower alkyl); —(CH₂)_(m)OCONR³³R⁷⁵ (where R³³ is H; or lower alkyl;or lower alkenyl; R⁷⁵ is lower alkyl; or R³³ and R⁷⁵ taken together are—(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—;where R⁵⁷ is H; or lower alkyl); —(CH₂)_(m)NR²⁰CONR³³R⁸¹ (where R²⁰ isH; or lower alkyl; R³³ is H; or lower alkyl; or lower alkenyl; R⁸¹ is H;or lower alkyl; or R³³ and R⁸¹ taken together are —(CH₂)₂₋₆—;—(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H;or lower alkyl); —(CH₂)_(m)N(R²⁰)COR⁶⁴ (where: R²⁰ is H; or lower alkyl;R⁶⁴ is lower alkyl; or lower alkenyl); —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷ islower alkyl; or lower alkenyl); —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸ is loweralkyl; or lower alkenyl; and R⁵⁹ is H; lower alkyl; or R⁵⁸ and R⁵⁹ takentogether are —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H; or lower alkyl); —(CH₂)_(o)PO(OR⁶⁰)₂(where R⁶⁰ is lower alkyl; or lower alkenyl); —(CH₂)_(o)SO₂R⁶² (whereR⁶² is lower alkyl; or lower alkenyl); or —(CH₂)_(q)C₆H₄R⁸ (where R⁸ isH; F; Cl; CF₃; lower alkyl; lower alkenyl; or lower alkoxy); or,alternatively, R²⁵ and R²⁶ taken together are —(CH₂)₂₋₆—;—(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR³⁴(CH₂)₂—; R²⁷ is H; loweralkyl; lower alkenyl; —(CH₂)_(o)OR⁵⁵ (where R⁵⁵ is lower alkyl; or loweralkenyl); —(CH₂)_(o)SR⁵⁶ (where R⁵⁶ is lower alkyl; or lower alkenyl);—(CH₂)_(o)NR³³R³⁴ (where R³³ is lower alkyl; or lower alkenyl; R³⁴ is H;or lower alkyl; or R³³ and R³⁴ taken together are —(CH₂)₂₋₆—;—(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H;or lower alkyl); —(CH₂)_(o)OCONR³³R⁷⁵ (where R³³ is H; or lower alkyl;or lower alkenyl; R⁷⁵ is lower alkyl; or R³³ and R⁷⁵ taken together are—(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—;where R⁵⁷ is H; or lower alkyl); —(CH₂)_(o)NR²⁰CONR³³R⁸¹ (where R²⁰ isH; or lower lower alkyl; R³³ is H; or lower alkyl; or lower alkenyl; R⁸¹is H; or lower alkyl; or R³³ and R⁸¹ taken together are —(CH₂)₂₋₆—;—(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H;or lower alkyl); —(CH₂)_(o)N(R²⁰)COR⁶⁴ (where R²⁰ is H; or lower alkyl;R⁶⁴ is lower alkyl; or lower alkenyl); —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷ islower alkyl; or lower alkenyl); —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸ is loweralkyl, or lower alkenyl; and R⁵⁹ is H; lower alkyl; or R⁵⁸ and R⁵⁹ takentogether are —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H; or lower alkyl); —(CH₂)_(o)PO(OR⁶⁰)₂(where R⁶⁰ is lower alkyl; or lower alkenyl); —(CH₂)_(o)SO₂R⁶² (whereR⁶² is lower alkyl; or lower alkenyl); or —(CH₂)_(q)C₆H₄R⁸ (where R⁶ isH; F; Cl; CF₃; lower alkyl; lower alkenyl; or lower alkoxy); R²⁸ islower alkyl; lower alkenyl; —(CH₂)_(o)OR⁵⁵ (where R⁵⁵ is lower alkyl; orlower alkenyl); —(CH₂)_(o)SR⁵⁶ (where R⁵⁶ is lower alkyl; or loweralkenyl); —(CH₂)_(o)NR³³R³⁴ (where R³³ is lower alkyl; or lower alkenyl;R³⁴ is H; or lower alkyl; or R³³ and R³⁴ taken together are —(CH₂)₂₋₆—;—(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H;or lower alkyl); —(CH₂)_(o)OCONR³³R⁷⁵ (where R³³ is H; or lower alkyl;or lower alkenyl; R⁷⁵ is lower alkyl; or R³³ and R⁷⁵ taken together are—(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—;where R⁵⁷ is H; or lower alkyl); —(CH₂)_(o)NR²⁰CONR³³R⁸¹ (where R²⁰ isH; or lower alkyl; R³³ is H; or lower alkyl; or lower alkenyl; R⁸¹ is H;or lower alkyl; or R³³ and R⁸¹ taken together are —(CH₂)₂₋₆—;—(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H;or lower alkyl); —(CH₂)_(o)N(R²⁰)COR⁶⁴(where: R²⁰ is H; or lower alkyl;R⁶⁴ is lower alkyl; or lower alkenyl); —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷ islower alkyl; or lower alkenyl); —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸ is loweralkyl, or lower alkenyl; and R⁵⁹ is H; lower alkyl; or R⁵⁸ and R⁵⁹ takentogether are —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H; or lower alkyl); —(CH₂)_(o)PO(OR⁶⁰)₂(where R⁶⁰ is lower alkyl; or lower alkenyl); —(CH₂)_(o)SO₂R⁶² (whereR⁶² is lower alkyl; or lower alkenyl); or —(CH₂)_(q)C₆H₄R⁸ (where R⁸ isH; F; Cl; CF₃; lower alkyl; lower alkenyl; or lower alkoxy); and R²⁹ islower alkyl; lower alkenyl; —(CH₂)_(o)OR⁵⁵ (where R⁵⁵ is lower alkyl; orlower alkenyl); —(CH₂)_(o)SR⁵⁶ (where R⁵⁶ is lower alkyl; or loweralkenyl); —(CH₂)_(o)NR³³R²⁴ (where R³³ is lower alkyl; or lower alkenyl;R³⁴ is H; or lower alkyl; or R³³ and R³⁴ taken together are —(CH₂)₂₋₆—;—(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H;or lower alkyl); —(CH₂)_(o)OCONR³³R⁷⁵ (where R³³ is H; or lower alkyl;or lower alkenyl; R⁷⁵ is lower alkyl; or R³³ and R⁷⁵ taken together are—(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—;where R⁵⁷ is H; or lower alkyl); —(CH₂)_(o)NR²⁰CONR³³R⁸¹ (where R²⁰ isH; or lower alkyl; R³³ is H; or lower alkyl; or lower alkenyl; R⁸¹ is H;or lower alkyl; or R²³ and R⁸¹ taken together are —(CH₂)₂₋₆—;—(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H;or lower alkyl); —(CH₂)_(o)N(R²⁰)COR⁶⁴ (where: R²⁰ is H; or lower alkyl;R⁶⁴ is lower alkyl; or lower alkenyl); —NR²⁰CO-lower-alkyl (R²⁰═H; orlower alkyl) being particularly favoured; —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷ islower alkyl; or lower alkenyl); —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸ is loweralkyl, or lower alkenyl; and R⁵⁹ is H; lower alkyl; or R⁵⁸ and R⁵⁹ takentogether are —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CM₂)₂—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H; or lower alkyl); —(CH₂)_(o)PO(OR⁶⁰)₂(where R⁶⁰ is lower alkyl; or lower alkenyl); —(CH₂)_(o)SO₂R⁶² (whereR⁶² is lower alkyl; or lower alkenyl); or —(CH₂)_(q)C₆H₄R⁸ (where R⁸ isH; F; Cl; CF₃; lower alkyl; lower alkenyl; or lower alkoxy). 8.Compounds according to claim 7 wherein R²³, R²⁴ and R²⁹ are —NR²⁰—CO-lower alkyl where R²⁰ is H; or lower alkyl.
 9. Compounds accordingto claim 7 or 8 wherein A is a group of one of the formulae A74 (withR²² being H); A75; A76; A77 (with R²² being H); A78; and A79. 10.Compounds according to any one of claims 2 to 9 wherein B is a group offormula —NR²⁰CH(R⁷¹)—, or —OCH(R⁷¹)— or —OCH(R⁷²)— or —OCH(R⁷⁸)— or—OCH(R⁷⁴)— or —OCH(R⁸⁴)—, or an enantiomer of one of the groups A5 (withR² being H); A8; A22; A25; A38 (with R² being H); A42; A47; and A50. 11.Compounds according to claim 10 wherein B—CO is Ala; Arg; Asn; Asp; Cys;Gin; Glu; Gly; His; Ile; Leu; Lys; Met; Phe; Pro; Ser; Thr; Trp; Tyr;Val; Cit; Orn; tBuA; Sar; t-BuG; 4AmPhe; 3AmPhe; 2AmPhe;Phe(mC(NH₂)═NH); Phe(pC(NR₂)═NH); Phe(mNHC(NH₂)═NH); Phe(pNHC(NH₂)═NH);Phg; Cha; C₄al; C₅al; Nle; 2-Nal; 1-Nal; 4Cl-Phe; 3Cl-Phe; 2Cl-Phe;3,4Cl₂Phe; 4F-Phe; 3F-Phe; 2F-Phe; Tic; Thi; Tza; Mso; AcLys; Dpr; A₂Bu;Dab; Abu; Aha; Aib; Y(Bzl); Bip; S(Bzl); T(Bzl); hCha; hCys; hSer, hArg;hPhe; Bpa; Pip; OctG; MePhe; MeNle; MeAla; MeIle; MeVal; MeLeu; 4Hyp1;4Hyp2; 4Mp1; 4Mp2; Oic; Glycolic acid; Lac; Hmb; H3mp; H4mp; Hmtb; Hhpp;Himp; Hpp; Hinp; Dhp; Hbd; Hpd; Ahh; Hgp; Hmcp; Haa; Hcp; Hcb; 3Dhb;Hpa; Ahp; Ahb; 3Ahb; 4Dhb; Hmcb; Hpb; Hcb; Hgh; Hcap; Ahp; Hdmp; Hdmb;Hchp; Hcbp; Hcpp; Hca; Hda; H2np; H1np; Hbp; 4Clphp; 3Clphp; 2Clphp;4Fphp; 3Fphp; 2Fphp; Aahh; Hbpp; Bhp; Bhb; Hbopp; 4Hb; 6Hh or Hib. 12.Compounds according to claim 10 or 11 wherein B is a group, having(L)-configuration, of formula

wherein R²⁰ is H; or lower alkyl; and R⁶⁴ is alkyl; alkenyl;—[(CH₂)_(u)—X]_(t)—CH₃, wherein X is —O—, —NR²⁰—, —S—; u=1-3, t=1-6;aryl; aryl-lower alkyl; or heteroaryl-lower alkyl.
 13. Compoundsaccording to claim 12 wherein R⁶⁴ is n-hexyl; n-heptyl;4-(phenyl)benzyl; diphenylmethyl,3-amino-propyl; 5-amino-pentyl; methyl;ethyl; isopropyl; isobutyl; n-propyl; cyclohexyl; cyclohexylmethyl;n-butyl; phenyl; benzyl; (3-indolyl)methyl; 2-(3-indolyl)ethyl;(4-phenyl)phenyl; n-nonyl; CH₃—OCH₂CH₂—OCH₂— or CH₃—(OCH₂CH₂)₂—OCH₂—.14. Compounds according to claim 1 wherein

is a group of formula (b1) to (c1); R¹ is H; or lower alkyl; R²⁰ is H;or lower alkyl; R³⁰ is H; or methyl; R³¹ is H; lower alkyl; loweralkenyl; —(CH₂)_(p)OR⁵⁵ (where R⁵⁵ is lower alkyl; or lower alkenyl);—(CH₂)_(p)NR³³R³⁴ (where R³³ is lower alkyl; or lower alkenyl; R³⁴ is H;or lower alkyl; or R³³ and R³⁴ taken together are —(CH₂)₂₋₆—;—(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H;or lower alkyl); —(CH₂)_(p)OCONR³³R⁷⁵ (where R³³ is H; or lower alkyl;or lower alkenyl; R⁷⁵ is lower alkyl; or R³³ and R⁷⁵ taken together are—(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—;where R⁵⁷ is H; or lower alkyl); —(CH₂)_(p)NR²⁰CONR³³R⁸¹ (where R²⁰ isH; or lower alkyl; R³³ is H; or lower alkyl; or lower alkenyl; R⁸¹ is H;or lower alkyl; or R³³ and R⁸¹ taken together are —(CH₂)₂₋₆—;—(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H;or lower alkyl); —(CH₂)_(p)N(R²⁰)COR⁶⁴ (where: R²⁰ is H; or lower alkyl;R⁶⁴ is lower alkyl; or lower alkenyl); —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷ islower alkyl; or lower alkenyl); —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸ is loweralkyl, or lower alkenyl; and R⁵⁹ is H; lower alkyl; or R⁵⁸ and R⁵⁹ takentogether are —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H; or lower alkyl); —(CH₂)_(o)PO(OR⁶⁰)₂(where R⁶⁰ is lower alkyl; or lower alkenyl); —(CH₂)_(o)SO₂R⁶² (whereR⁶² is lower alkyl; or lower alkenyl); or —(CH₂)_(r)C₆H₄R⁸ (where R⁸ isH; F; Cl; CF₃; lower alkyl; lower alkenyl; or lower alkoxy); mostpreferably —CH₂CONR⁵⁸R⁵⁹ (where R⁵⁸ is H; or lower alkyl; and R⁵⁹ islower alkyl; or lower alkenyl); R³² is H; or methyl; R³³ is lower alkyl;lower alkenyl; —(CH₂)_(m)OR⁵⁵ (where R⁵⁵ is lower alkyl; or loweralkenyl); —(CH₂)_(m)NR³⁴R⁶³ (where R³⁴ is lower alkyl; or lower alkenyl;R⁶³ is H; or lower alkyl; or R³⁴ and R⁶³ taken together are —(CH₂)₂₋₆—;—(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H;or lower alkyl); —(CH₂)_(m)OCONR⁷⁵R⁸² (where R⁷⁵ is lower alkyl; orlower alkenyl; R⁸² is H; or lower alkyl; or R⁷⁵ and R⁸² taken togetherare —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—;where R⁵⁷ is H; or lower alkyl); —(CH₂)_(m)NR²⁰CONR⁷⁸R⁸² (where R²⁰ isH; or lower alkyl; R⁷⁸ is H; or lower alkyl; or lower alkenyl; R⁸² is H;or lower alkyl; or R⁷⁸ and R⁸² taken together are —(CH₂)₂₋₆—;—(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H;or lower alkyl); —(CH₂)_(m)N(R²⁰)COR⁶⁴ (where: R²⁰ is H; or lower alkyl;R⁶⁴ is lower alkyl; or lower alkenyl); —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷ islower alkyl; or lower alkenyl); —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸ is loweralkyl; or lower alkenyl; and R⁵⁹ is H; lower alkyl; or R⁵⁸ and R⁵⁹ takentogether are —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); R³⁴ is H; or loweralkyl; R³⁵ is H; lower alkyl; lower alkenyl; (CH₂)_(m)OR⁵⁵ (where R⁵⁵:lower alkyl; or lower alkenyl); —(CH₂)_(m)NR³³R³⁴ (where R³³ is loweralkyl; or lower alkenyl; R³⁴ is H; or lower alkyl; or R³³ and R³⁴ takentogether are —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H; or lower alkyl);—(CH₂)_(m)OCONR³³R^(θ)(where R³³ is H; or lower alkyl; or lower alkenyl;R⁷⁵ is lower alkyl; or R³³ and R⁷⁵ taken together are —(CH₂)₂₋₆—;—(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H;or lower alkyl); —(CH₂)_(m)NR²⁰CONR³³R⁸¹ (where R²⁰ is H; or loweralkyl; R³³ is H; or lower alkyl; or lower alkenyl; R⁸¹ is H; or loweralkyl; or R³³ and R⁸¹ taken together are —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;—(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H; or lower alkyl);—(CH₂)_(m)N(R²⁰)COR⁶⁴ (where: R²⁰ is H; or lower alkyl; R⁶⁴ is loweralkyl; or lower alkenyl); —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷ is lower alkyl; orlower alkenyl); —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸ is lower alkyl; or loweralkenyl; and R⁵⁹ is H; lower alkyl; or R⁵⁸ and R⁵⁹ taken together are—(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—;where R⁵⁷ is H; or lower alkyl); R³⁶ is lower alkyl; lower alkenyl; oraryl-lower alkyl; R³⁷ is H; lower alkyl; lower alkenyl; —(CH₂)_(p)OR⁵⁵(where R⁵⁵ is lower alkyl; or lower alkenyl); —(CH₂)_(p)NR²³R³⁴ (whereR³³ is lower alkyl; or lower alkenyl; R³⁴ is H; or lower alkyl; or R³³and R³⁴ taken together are —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—;or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H; or lower alkyl);—(CH₂)_(p)OCONR³³R⁷⁵ (where R³³ is H; or lower alkyl; or lower alkenyl;R⁷⁵ is lower alkyl; or R³³ and R⁷⁵ taken together are —(CH₂)₂₋₆—;—(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H;or lower alkyl); —(CH₂)_(p)NR²⁰CONR³³R⁸¹ (where R²⁰ is H; or loweralkyl; R³³ is H; or lower alkyl; or lower alkenyl; R⁸¹ is H; or loweralkyl; or R³³ and R⁸¹ taken together are —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;—(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H; or lower alkyl);—(CH₂)_(p)N(R²⁰)COR⁶⁴ (where: R²⁰ is H; or lower alkyl; R⁶⁴ is loweralkyl; or lower alkenyl); —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷ is lower alkyl; orlower alkenyl); —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸ is lower alkyl, or loweralkenyl; and R⁵⁹ is H; lower alkyl; or R⁵⁸ and R⁵⁹ taken together are—(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—;where R⁵⁷ is H; or lower alkyl); —(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰ is loweralkyl; or lower alkenyl); —(CH₂)_(o)SO₂R⁶² (where R⁶² is lower alky; orlower alkenyl); or —(CH₂)_(q)C₆H₄R⁸ (where R⁸ is H; F; Cl; CF₃; loweralkyl; lower alkenyl; or lower alkoxy); and R³⁸ is H; lower alkyl; loweralkenyl; —(CH₂)_(p)OR⁵⁵ (where R⁵⁵ is lower alkyl; or lower alkenyl);—(CH₂)_(p)NR³³R³⁴ (where R³³ is lower alkyl; or lower alkenyl; R³⁴ is H;or lower alkyl; or R³³ and R³⁴ taken together are —(CH₂)₂₋₆—;—(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H;or lower alkyl); —(CH₂)_(p)OCONR³³R⁷⁵ (where R³³ is H; or lower alkyl;or lower alkenyl; R⁷⁵ is lower alkyl; or R³³ and R⁷⁵ taken together are—(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—;where R⁵⁷ is H; or lower alkyl); —(CH₂)_(p)NR²⁰CONR³³R⁸¹ (where R²⁰ isH; or lower alkyl; R³³ is H; or lower alkyl; or lower alkenyl; R⁸¹² isH; or lower alkyl; or R³³ and R⁸¹ taken together are —(CH₂)₂₋₆—;—(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H;or lower alkyl); —(CH₂)_(p)N(R²⁰)COR⁶⁴ (where: R²⁰ is H; or lower alkyl;R⁶⁴ is lower alkyl; or lower alkenyl); —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷ islower alkyl; or lower alkenyl); —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸ is loweralkyl, or lower alkenyl; and R⁵⁹ is H; lower alkyl; or R⁵⁸ and R⁵⁹ takentogether are —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or—(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷ is H; or lower alkyl); —(CH₂)_(o)PO(OR⁶⁰)₂(where R⁶⁰ is lower alkyl; or lower alkenyl); —(CH₂)_(o)SO₂R⁶² (whereR⁶² is lower alkyl; or lower alkenyl); or —(CH₂)_(q)C₆H₄R⁸ (where R⁸ isH; F; Cl; CF₃; lower alkyl; lower alkenyl; or lower alkoxy). 15.Compounds according to claim 14 wherein R¹ is H; R²⁰ is H; R³⁰ is H; R³¹is carboxymethyl; or lower alkoxy-carbonylmethyl; R³² is H; R³⁵ ismethyl; R³⁶ is methoxy; R³⁷ is H and R³⁸ is H.
 16. Compounds accordingto claim 2 wherein the template is ^(D)Pro-^(L)Pro or ^(L)Pro-^(D)Pro ora group corresponding thereto but in which the ^(D)Pro moiety and/or the^(L)Pro moiety is substituted as shown in Formula A8′ and, respectively,A8″, as defined in claim 5 and, respectively, in claim
 12. 17. Compoundsaccording to any one of claims 1 to 16 wherein the α-amino and/orα-hydroxy acid residues in positions 1 to 14 in the chain Z are: P1: oftype D or of type L; P2: of type D or of type L; P3: of type C, type Dor of type L; P4: of type F; P5: of type E, type F or of type L; P6: oftype C or of type L; P7: of formula -A-CO—, Gly or Pro P8: of type E orof type L; P9: of type E; P10: of type D; P11: of type F; P12: of type Dor of type L; P13: of type F or of type L; and P14: of type E or of typeL; or P4 and P11, taken together, can form a group of type H; at P5, P7and P13 also D-isomers being possible.
 18. Compounds according to claim17 wherein the α-amino and/or α-hydroxy acid residues in positions 1 to14 of the chain Z are: P1: Tyr, Hhpp; P2: His, Ahb; P3: Ala, Lac; P4:Cys; P5: Ser, Ahb, ^(D)Ser, Arg; P6: Lac, Ala; P7: ^(D)Pro; P8: Dab,Ahb; P9: Arg; P10: Tyr; P11: Cys; P12: Tyr, Hhpp; P13: Gln, Hhpp,^(D)Gln; P14: Lys, Ahb; formation of a disulfide bridge being possiblebetween the Cys residues at P4 and P11.
 19. A compound of formula Iaaccording to claim 1 wherein the template is ^(D)Pro-^(L)Pro, and theresidues in position 1-14 of the chain Z are: P1: Tyr; P2: His; P3: Ala;P4: Cys; P5: Ser; P6: Lac; P7: ^(D)Pro; P8: Dab; P9: Arg; P10: Tyr; P11:Cys; P12: Tyr; P13: Gln; and P14: Lys; Cys at P4 and P11 forming adisulfide bridge.
 20. A compound of formula Ia according to claim 1wherein the template is ^(D)Pro-^(L)Pro, and the residues in position1-14 of the chain Z are: P1: Tyr; P2: His; P3: Ala; P4: Cys; P5: Ser;P6: Ala; P7: ^(D)Pro; P8: Dab; P9: Arg; P10: Tyr; P11: Cys; P12: Hhpp;P13: Gln; and P14: Lys; Cys at P4 and P11 forming a disulfide bridge.21. A compound of formula Ia according to claim 1 wherein the templateis ^(D)Pro-^(L)Pro, and the residues in position 1-14 of the chain Zare: P1: Tyr; P2: His; P3: Ala; P4: Cys; P5: ^(D)Ser; P6: Lac; P7:^(D)Pro; P8: Dab; P9: Arg; P10: Tyr; P11: Cys; P12: Tyr; P13: Gln; andP14: Lys; Cys at P4 and P11 forming a disulfide bridge.
 22. Enantiomersof the compounds of formula Ia or Ib as defined in claim
 1. 23.Compounds according to any one of claims 1 to 22 for use astherapeutically active substances.
 24. Compounds according to claim 23having CXCR4 antagonizing activity and/or anticancer activity and/oranti inflammatory activity.
 25. A pharmaceutical composition containinga compound according to any one of claims 1 to 22 and a pharmaceuticallyinert carrier.
 26. Compositions according to claim 25 in a form suitablefor oral, topical, transdermal, injection, buccal, transmucosal,pulmonary or inhalation administration.
 27. Compositions according toclaim 25 or 26 in form of tablets, dragees, capsules, solutions,liquids, gels, plaster, creams, ointments, syrup, slurries, suspensions,spray, nebuliser or suppositories.
 28. The use of compounds according toany one of claims 1 to 22 for the manufacture of a CXCR4 antagonizingmedicament.
 29. The use according to claim 28 wherein said CXCR4antagonizing medicament is intended to be used for preventing HIVinfections in non-infected individuals or for slowing and halting viralprogression in infected patients; or where cancer is mediated orresulting from; or where an immunological disease are mediated orresulting from CXCR4 receptor activity; or for treating immunosuppression; or during apheresis collections of peripheral blood stemcells and/or as agents to induce mobilization of stem cells to regulatetissue repair.
 30. A process for the manufacture of compounds accordingto any one of claims 1-21 which process comprises (a) coupling anappropriately functionalized solid support with an appropriatelyN-protected derivative of that amino acid or an appropriatelyO-protected derivative of that hydroxy acid which in the desiredend-product is in positions 3, 5, 6, 7, 8 or 10, any functional groupwhich may be present in said N-protected amino acid derivative orO-protected hydroxy acid derivative being likewise appropriatelyprotected; (b) removing the N-protecting or O-protecting group from theproduct thus obtained; (c) coupling the product thus obtained with anappropriately N-protected derivative of that amino acid or anappropriately O-protected derivative of that hydroxy acid which in thedesired end-product is one position nearer the N-terminal amino acidresidue or O-terminal hydroxy acid residue, any functional group whichmay be present in said N-protected amino acid derivative or O-protectedhydroxy acid derivative being likewise appropriately protected; (d)removing the N-protecting group or O-protecting group from the productthus obtained; (e) repeating steps (c) and (d) until the N-terminalamino acid residue or O-terminal hydroxy acid residue has beenintroduced; (f) coupling the product thus obtained with one of thecompounds of the general formulae

wherein

is as defined in claim 1 and X is an N-protecting group and,respectively, an O-protecting group; or, alternatively, if

is to be group (a1) or (a2) as defined in claim 1, (fa) coupling theproduct obtained in step (e) with an appropriately N-protectedderivative of an amino acid or an appropriately O-protected derivativeof a hydroxy acid of the general formulaHOOC-B-H   III orHOOC-A-H   IV wherein B and A are as defined in claim 1, any functionalgroup which may be present in said N-protected amino acid derivative orO-protected hydroxy acid derivative being likewise appropriatelyprotected; (fb) removing the N-protecting group or O-protecting groupfrom the product thus obtained; and (fc) coupling the product thusobtained with an appropriately N-protected derivative of an amino acidor an appropriately O-protected derivative of a hydroxy acid of theabove general formula IV and, respectively, III, any functional groupwhich may be present in said N-protected amino acid derivative orO-protected hydroxy acid derivative being likewise appropriatelyprotected; (g) removing the N-protecting group or O-protecting groupfrom the product obtained in step (f) or (fc); (h) coupling the productthus obtained with an appropriately N-protected derivative of that aminoacid or an appropriately O-protected derivative of that hydroxy acidwhich in the desired end-product is in position 14, any functional groupwhich may be present in said N-protected amino acid derivative orO-protected hydroxy acid derivative being likewise appropriatelyprotected; (i) removing the N-protecting group or O-protecting groupfrom the product thus obtained; (j) coupling the product thus obtainedwith an appropriately N-protected derivative of that amino acid or anappropriately O-protected derivative of that hydroxy acid which in thedesired end-product is one position farther away from position 14, anyfunctional group which may be present in said N-protected amino acidderivative or O-protected hydroxy acid derivative being likewiseappropriately protected; (k) removing the N-protecting group orO-protecting group from the product thus obtained; (l) repeating steps(j) and (k) until all amino acid or hydroxy acid residues have beenintroduced; (m) if desired, selectively deprotecting one or severalprotected functional group(s) present in the molecule and appropriatelysubstituting the reactive group(s) thus liberated; (n) if desired,forming an interstrand linkage between side-chains of appropriate aminoacid residues at positions P4 and P11; (o) detaching the product thusobtained from the solid support; (p) cyclizing the product cleaved fromthe solid support; (q) removing any protecting groups present onfunctional groups of any members of the chain of amino acid and/orhydroxy acid residues and, if desired, any protecting group(s) which mayin addition be present in the molecule; and (r) if desired, convertingthe product thus obtained into a pharmaceutically acceptable salt orconverting a pharmaceutically acceptable, or unacceptable, salt thusobtained into the corresponding free compound of formula Ia or Ib orinto a different, pharmaceutically acceptable, salt.
 31. A process forthe manufacture of compounds according to any one of claims 1-21 whichprocess comprises (a′) coupling an appropriately functionalized solidsupport with one of the compounds of the general formulae

wherein

is as defined in claim 1 and X is an N-protecting group or anO-protecting group, or, alternatively, if

is to be group (a1) or (a2)as defined in claim 1, (a′a) coupling saidappropriately functionalized solid support with an appropriatelyN-protected derivative of an amino acid or an appropriately O-protectedderivative of a hydroxy acid of the general formulaHOOC-B-H   III orHOOC-A-H   IV wherein B and A are as defined in claim 1, any functionalgroup which may be present in said N-protected amino acid derivative orO-protected hydroxy acid derivative being likewise appropriatelyprotected; (a′b) removing the N-protecting group or O-protecting groupfrom the product thus obtained; and (a′c) coupling the product thusobtained with an appropriately N-protected derivative of an amino acidor an appropriately O-protected derivative of a hydroxy acid of theabove general formula IV and, respectively, III, any functional groupwhich may be present in said N-protected amino acid derivative orO-protected hydroxy acid derivative being likewise appropriatelyprotected; (b′) removing the N-protecting group or O-protecting groupfrom the product obtained in step (a′) or (a′c) (c′) coupling theproduct thus obtained with an appropriately N-protected derivative ofthat amino acid or an appropriately O-protected derivative of thathydroxy acid which in the desired end-product is in position 14, anyfunctional group which may be present in said N-protected amino acidderivative or O-protected hydroxy acid derivative being likewiseappropriately protected; (d′) removing the N-protecting group orO-protecting group from the product thus obtained; (e′) coupling theproduct thus obtained with an appropriately N-protected derivative ofthat amino acid or an appropriately O-protected derivative of thathydroxy acid which in the desired end-product is one position fartheraway from position 14, any functional group which may be present in saidN-protected amino acid derivative or O-protected hydroxy acid derivativebeing likewise appropriately protected; (f′) removing the N-protectinggroup or O-protecting group from the product thus obtained; (g′)repeating steps (e′) and (f′) until all amino acid or hydroxy acidresidues have been introduced; (h′) if desired, selectively deprotectingone or several protected functional group(s) present in the molecule andappropriately substituting the reactive group(s) thus liberated; (i′) ifdesired forming an interstrand linkage between side-chains ofappropriate amino acid residues at positions P4 and P11; (j′) detachingthe product thus obtained from the solid support; (k′) cyclizing theproduct cleaved from the solid support; (l′) removing any protectinggroups present on functional groups of any members of the chain of aminoacid and/or hydroxy acid residues and, if desired, any protectinggroup(s) which may in addition be present in the molecule; and (m′) ifdesired, converting the product thus obtained into a pharmaceuticallyacceptable salt or converting a pharmaceutically acceptable, orunacceptable, salt thus obtained into the corresponding free compound offormula Ia or Ib or into a different, pharmaceutically acceptable, salt.32. A process for the manufacture of those compounds according to claim1 in which

is to be group (a1) or (a2) as defined in claim 1, which processcomprises (a″a) coupling an appropriately functionalized solid supportwith an appropriately N-protected derivative of an amino acid or anappropriately O-protected derivative of a hydroxy acid of the generalformulaHOOC-A-H   IV orHOOC-B-H III wherein A and B are as defined in claim 1, any functionalgroup which may be present in said N-protected amino acid derivative orO-protected hydroxy acid derivative being likewise appropriatelyprotected; (a″b) removing the N-protecting group or O-protecting groupfrom the product thus obtained; (b″)coupling the product thus obtainedwith an appropriately N-protected derivative of that amino acid or anappropriately O-protected derivative of that hydroxy acid which in thedesired end-product is in position 14, any functional group which may bepresent in said N-protected amino acid derivative or O-protected hydroxyacid derivative being likewise appropriately protected; (c″) removingthe N-protecting group or O-protecting group from the product thusobtained; (d″)coupling the product thus obtained with an appropriatelyN-protected derivative of that amino acid or an appropriatelyO-protected derivative of that hydroxy acid which in the desiredend-product is one position farther away from position 14, anyfunctional group which may be present in said N-protected amino acidderivative or O-protected hydroxy acid derivative being likewiseappropriately protected; (e″) removing the N-protecting group orO-protecting group from the product thus obtained; (f″) repeating steps(d″) and (e″) until all amino acid or hydroxy acid residues of the chainZ have been introduced; (g″) coupling the product thus obtained with anappropriately N-protected derivative of an amino acid or anappropriately O-protected derivative of a hydroxy acid of the abovegeneral formula III and, respectively, IV, any functional group whichmay be present in said N-protected amino acid derivative or O-protectedhydroxy acid derivative being likewise appropriately protected; (h″)removing the N-protecting group or O-protecting group from the productobtained in step ((g″) (i″) if desired, selectively deprotecting one orseveral protected functional group(s) present in the molecule andappropriately substituting the reactive group(s) thus liberated; (j″) ifdesired forming an interstrand linkage between side-chains ofappropriate amino acid residues at positions P4 and P11; (k″) detachingthe product thus obtained from the solid support; (l″) cyclizing theproduct cleaved from the solid support; (m″) removing any protectinggroups present on functional groups of any members of the chain of aminoacid and/or hydroxy acid residues and, if desired, any protectinggroup(s) which may in addition be present in the molecule; and (n″) ifdesired, converting the product thus obtained into a pharmaceuticallyacceptable salt or converting a pharmaceutically acceptable, orunacceptable, salt thus obtained into the corresponding free compound offormula Ia or Ib or into a different, pharmaceutically acceptable, salt.33. A modification of the processes according to any one of claims 30 to32 for the manufacture of compounds according to claim 22 in whichenantiomers of all chiral starting materials are used.